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BSI EXAM 2 Flashcards

1
Q

What are GPRs? (sometimes called GPCRs).

A

G-protein receptors (or G-protein Coupled receptors) which activate heterotrimeric G-proteins intracellularly after binding the messenger extracellularly

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2
Q

What are RTKs?

A

Receptor tyrosine kinases which dimerize and phosphorylate each other (intracellularly) after binding the specific messenger (extracellularly); they either directly activate kinase cascades or act via low molecular weight G-proteins.

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3
Q

What are RTKs? Functions?

A

These signal transduction pathways can affect all aspects of cell function from synaptic transmission to gene transcription. They allow cells to integrate their functions effectively and are obviously very important pharmacological targets.

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4
Q

What are G-proteins?

A

They are sites of signal transduction pathway integration and regulation; these pathways are not linear and cross-talk extensively. There are 2 main types; heterotrimeric G-proteins have 3 subunits and are self-limiting (on a timer) whereas low molecular weight G-proteins (LMW G-proteins; also called monomeric) have one subunit and need accessory proteins to turn them off. Heterotrimerics are activated by GPR’s whereas LMW G-proteins need RTK’s plus additional accessory proteins to be activated.

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5
Q

Why are they called G-proteins?

A

Because they bind guanosine nucleotides; both LMW G-proteins and the -subunit of heterotrimerics bind GDP when inactive and GTP when activated.

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6
Q

What is a secondary messenger?

A

A small molecule such as cAMP which is produced intracellularly in response to a messenger and diffuses across the cell affecting target proteins such as enzymes and ion channels.

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7
Q

What is the most well-known secondary messenger?

A

OOPS! Try cAMP (but also cGMP and Ca2+).

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8
Q

What is a GEF?

A

A Guanosine Exchange Factor; this is the activated GPR for heterotrimerics and the dimerized (so active) RTK’s c/w other proteins AND the specific GEF. As the name suggests, these allow the exchange of bound GDP (inactive) for GTP (active).

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9
Q

What is a GAP?

A

A GTP’ase Activating Protein; this is intrinsic in the -subunit (heterotrimerics; self-limiting) but must be supplied via a separate accessory protein for LMW G-proteins.

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10
Q

What is a GIP?

A

A GTP’ase Inhibiting Protein; they antagonize GAP’s so keeping LMW G-proteins turned on.

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11
Q

What is a GDI?

A

A Guanosine nucleotide Dissociation Inhibitor; currently only associated with LMW G-proteins where they antagonize GEF’s so keeping LMW G-proteins turned off.

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12
Q

The cell secreted by ___ ____ ____ to affect other neurons or “_____” such as muscles and glands (neurotransmitters)

A

neurons across synapses; effectors

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13
Q

These messengers can affect every aspect of cell function from what? (4)

A

growth
differentiation to metabolism
processing of data
programmed cell death (apoptosis)

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14
Q

2nd messengers

A

= AC (adenylyl cyclase)

intercellularly response to the chemical messenger

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15
Q

AC (adenylyl cyclase)

A

produces many molecules of cAMP which can affect target proteins so acting as amplification stage

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16
Q

Some chemical messengers are able to cross the memebrane (_____ ____) but are still recognized by ______ ________ receptors or enzymes such as (4)

A 
hydrophobic molecules 
specific intraceullar 
steroid hormones
thyroid hormones
t3,t4
nitric oxide (NO) and carbon monoxide (CO)
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17
Q

Receptor

A

specific protein in either the plasma membrane or interior of a target cell that a messenger combines with.

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18
Q

Specificity

A

the ability of a receptor to bind only one type or a limited number of structurally related types of chemical messengers

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19
Q

Saturation; If all are occupied, 100 saturation. If 50% are occupied, 50% saturation. ETC

A

the degree to which receptors are occupied by messengers.

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20
Q

Affinity

A

the strength with which a chemical messenger binds to its receptor.

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21
Q

Competition

A

the ability of different molecules that are very similar in structure to compete with each other to combine with the same receptor.

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22
Q

Agonist

A

a chemical messenger that binds to a receptor and triggers the cell’s response; often refers to a drug that mimics a normal messenger’s action.

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23
Q

Down-regulation

A

a decrease in the total number of target-cell receptors for a given messenger; may occur in response to chronic high extracellular concentration of the messenger.

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24
Q

Up-regulation

A

an increase in the total number of target-cell receptors for a given messenger; may occur in response to chronic low extracellular concentration of the messenger

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25
Q

Supersensitivity

A

the increased responsiveness of a target cell to a given messenger; may result from up-regulation of receptors.

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26
Q

Chemical messengers are sent throughout the body via circulation is _________

A

Endocrine

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27
Q

Chemical messengers act locally on adjacent cells is _______

A

Paracrine

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28
Q

Chemical messengers acting on the cell that secreted it is _____

A

Autocrine

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29
Q

Chemical messengers released across a synapse from a neuron is _________

A

Neurotransmitter (neuronal)

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30
Q

T or F? Cells in the body are subject to only ONE messenger at a time.

A

False. Typically cells are exposed to a constantly changing “cocktail” of chemical mediators whose effects may change as the target cell itself does.

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31
Q

T or F? Kinases phosphorolates a specific protein after being activated by a specific pathway.

A

True

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32
Q

T or F? Kinase phosphorolates a target protein, turning them on.

A

False, it can turn it either on or off.

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33
Q

T or F? Signal transduction is a linear path?

A

False, there are extensive convergence and divergence of pathways producing significant “cross-talk” between pathways which is necessary to integrate cell function.

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34
Q

Mechanism 1 is the simplest as the specific cell surface receptor is also a(n) _____ ______.

A

Ion Channel

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35
Q

Mech 1: Upon binding the messenger, the ion channel normally ______ but may ______ them.

A

Opens; close

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36
Q

Secondary Messengers

A

molecules produced inside the cell that causes a response.

Calcium, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) are examples.

Sometimes calcium (Ca2+) enters a cell through Mech 1, and binds to, activate, specific calcium binding proteins intracellularly, (such as Calmodulin). Calcium is acting

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37
Q

T or F? Calcium is produced and acts as a secondary messenger.

A

False, calcium is released not produced.

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38
Q

ionotropic receptor

A

Nicotinic Acetylcholine Receptor (nAChR) found at neuromuscular junctions, (skeletal muscle), autonomic ganglia and in the brain.

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39
Q

What are the 2 classes acetylcholine receptors?

A

Nicotinic and Muscarinic

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40
Q

Protein recap: If molecule A and molecule B are poorly matched and have only a few week bonds between them, what rapidly breaks them apart?

A

Thermal Motion

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41
Q

Does metabotropic receptors affect membrane potential directly?

A

No, Ionotropics does.

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42
Q

Does ionotropic receptors utilize g-proteins or significant signal transduction pathways?

A

No, metabotropic does.

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43
Q

Metabotropic

A

receptors are indirectly linked to protein channels.

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44
Q

T or F? Mech 1 does not cause a change in membrane potential.

A

False.

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45
Q

Can 2 proteins interact and affect their activities?

A

Yes

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46
Q

G-Protein Receptors (or G-protein Coupled receptors)

A

receptors which activate heterotrimeric G-proteins intracellularly after binding the messenger extracellularly.

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47
Q

Receptor tyrosine kinases (RTKs)

A

receptors which dimerize and phosphorylate each other (intracellularly) after binding the specific messenger (extracellularly); they either directly activate kinase cascades or act via low molecular weight G-proteins.

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48
Q

G-Proteins

A

sites of signal transduction pathway integration and regulation; these pathways are not linear and cross-talk extensively.

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49
Q

Heterotrimeric G-proteins

A

have 3 subunits and are self-limiting (on a timer), are activated by GPR’s

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50
Q

What are the 2 types of G-Proteins?

A

Heterotrimeric and Low molecular weight

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51
Q

Low molecular weight G-proteins

A

(also called monomeric) have one subunit and need accessory proteins to turn them off. These need RTK’s plus additional accessory proteins to be activated.

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52
Q

Why are G-proteins called G-proteins?

A

Because they bind guanosine nucleotides; both LMW G-proteins and the alpha-subunit of heterotrimerics bind GDP when inactive and GTP when activated.

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53
Q

What are the 3 subunits of heterotrimeric G-proteins?

A

Alpha, Beta, Gamma

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54
Q

T or F? Ligand/Agonist binds to the G-protein, then the alpha subunit from the GPR affects the effector protein.

A

False, GPR then G-protein

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55
Q

T or F? Heterotrimeric G-proteins can either directly interact with effectors or affect the production of secondary messengers.

A

True.

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56
Q

Mech 2

A

involved in mediating the actions of many neurotransmitters, , most peptide hormones, , and Adrenaline, (aka Epinephrine)

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57
Q

Recognition sites.

A

Extracellular N-terminal plus extracellular “loops” which link the TMDs together forms what on the GPRs

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58
Q

Where does Kinase get their phosphate from to phosphoralate?

A

ATP

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59
Q

Mech 2: Phosphoralation of specialized proteins in the intracellular C-terminal can do what to the GPR?

A

Turn off or desensitize

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60
Q

How are heterotrimeric G-protein tethered to the inner face of the cell membrane?

A

By lipid “tails” positioned adjacent to the GPR

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61
Q

Which of the subunits (alpha or Beta-Gamma) affects effectors?

A

They both can.

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62
Q

T or F? G-Protein Alpha-subunit in its inactive form binds to ADP

A

False, GDP

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63
Q

Which subunit of a heterotrimeric G-protein is the primary effector?

A

Alpha (but not solely)

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64
Q

Heterotrimeric G-proteins: Alpha subnit has binding sites for ______ nucleotides.

A

Guanine

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65
Q

Guanine Exchange Factor (GEF)

A

After the GPR is activated, there is a translocation through the protein whose intracellular part now becomes

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66
Q

T or F? GEF synthesizes GTP from GDP.

A

False, they exchange.

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67
Q

How does the alpha subunit becoming inactive again?

A

Due to the intrinsic GTPase activity and hydrolyzes the bound GTP back to GDP + phosphate. which inactivates the alpha-subunit which then re-associates with the beta-gamma-subunit so inactivating it too.

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68
Q

T or F? All heterotrimeric G-proteins are expressed ubiquitously in all cells and are involved in fundamental/universal cellular functions.

A

False. Only some are not all. Some G-proteins are only found in specialized cells where they are part of that specialized function.

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69
Q

There are hundreds of GPRs involved in odor discrimination but the cells expressing these receptors only contain _____ type of G-protein involved in odor perception.

A

ONE. (Golf: not found in any other cell type): specificity is given by the GPR and specific “wiring” of the neurons into the brain.

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70
Q

The most well know ubiquitous secondary messengers are the cAMP, how are they synthesized?

A

By adenylyl cyclases (AC) from ATP when it is stimulated by Alphas(s) subunit. (sub “s” denotes stimulatory”

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71
Q

How are cAMP removed?

A

By phosphodiesterases,, turns cAMP to AMP

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72
Q

How are cyclic guanine monophosphate (cGMP) generated?

A

By Guanylyl cyclase.(GC)

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73
Q

How are Diacylglycerol (DAG) and inositol 1,4,5-triphosphate generated?

A

By phospholipase C (PLC) cleaving PIP2

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74
Q

What are the 5 common secondary messenger?

A

cAMP, cGMP, DAG, IP3, Ca2+

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75
Q

How are cAMP or cGMP inactivated or removed?

A

By the phosphodiesterases

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76
Q

Phosphodiesterases, can they be regulated?

A

Yes

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77
Q

T or F? Signaling pathways: the actual “amount” of a secondary messenger is usually determined by the relative activity of both the synthesizing/activating and degrading/inactivating enzymes, producing graded responses rather than either “on” or “off.”

A

True

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78
Q

T or F?: Mech 3: The metabotropic receptors are GPRs.

A

False, they are Receptor Tyrosine Kinases (RTK)

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79
Q

T or F? RTKs when activated becomes phosphoralated and either directly activate other kinases or via adapter/docking proteins, or activate a different type of G-protein, the Low Molecular Weight G-proteins. (LMW G-proteins aka momomeric G-protein)

A

True.

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80
Q

How many domains does RTKs have?

A

One, but is often not functional until the binding of the messenger extracellularly brings 2 receptors close together “dimerization

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81
Q

How do RTKs dimerize?

A

When the primary messenger binds to RTK. Intracellularly this now allows each RTK to cross phosphorylate its partner at specific tyrosine residues.

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82
Q

kinase cascades

A

Auto cross phosphorylation of specific tyrosine residues on the RTKs intracellularly leads to the binding/activation

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83
Q

T or F? RTKs when activated, allows the binding/activation of kinase cascades sometimes involving LMW, G-proteins typified by Ras

A

True

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84
Q

Apart from direct activation of kinases, RTKs can often via adapter/docking protein recruit to the membrane ____ ___-____

A

LMW G-Protein

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85
Q

T or F? LMW G-protein has no intrinsic enzymatic activity.

A

True

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86
Q

GEF

A

Mech 3: Adaptor protein recruit LMW G-protein to the membrane, this in turns act as a ____, activating an inactive Ras protein which sends an onward transmission of signal.

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87
Q

The different pathways are very important as they often regulate the fundamental processes like _____ and _______

A

growth; differentiation

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88
Q

Kinases covalently

A

modify specific AA residues in target proteins which alters their activity and/or what they can bind to or interact with.

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89
Q

RTKs: The phophoralated tyrosine residues by tyrosine kinases is reversed by _______

A

Phosphatases

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90
Q

How are phophatases regulated?

A

Phosphodiesterases

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91
Q

Phosphorylation

A

specific tyrosine residues intracellularly on RTKs allows binding of certain proteins that would not bind prior to this process.

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92
Q

Family Proteins: Rho

A

Cytoskeleton

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93
Q

Family Proteins: Rac

A

cellular stress

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94
Q

Family Proteins: Ras

A

Growth

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95
Q

Family Proteins: Rab

A

Vesicle transport and exocytosis

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96
Q

Family Proteins: Ran

A

Nuclear trafficking

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97
Q

What is the G-Protein regulatory cycle?

A

4 different types of accessory proteins that essential competes to turn on and off GTP (GAPs(on);GIPs(off)) and GDP (GEFs(on);GDIs(off))

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98
Q

Monomeric G-proteins

A

LMW G-proteins

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99
Q

Monomeric G-proteins have only one subunit that is like a truncated heterotrimeric alpha subunit: They turn themselves off by means of……

A

accessory proteins

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100
Q

GTPase activity is supplied by _________. Without these the LMW G-protein remains permanently “on”.

A

GAP

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101
Q

What does constitutively active mean?

A

Permanently on

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102
Q

T or F? LMW G-proteins can be influenced by 4 different types of of accessory proteins.

A

True

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103
Q

T or F? Accessory proteins are subject to regulation and “talk” to/intergrate with other proteins involved in other signal translation pathways.

A

False, transduction pathways

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104
Q

kinase cascades

A

Most of these pathways involve _______ _______ where one activated kinase phosphorylates the next in the sequenece so activating it and so on

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105
Q

Transcription

A

The end result of kinase cascades often is an effect on

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106
Q

T or F? Phosphoralation can only turn on a protein.

A

False, it can also turn them off.

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107
Q

A lipid soluble messengers

A

do not want to go into the blood, they solubilized to an extent by binding to plasma protein.

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108
Q

Lipids soluble messengers can go into the cell and cannot be ________ down

A

broken

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109
Q

Some chemical messengers can cross the cell membrane and these are recognized by intracellular receptors either in the cytoplasm or nucleus itself: Name them.

A

Steroid hormones: Aldosterone, cortisol, testosterone, progesterone and the estrogens
Thyroid hormones: thyroxine and triiodothyronine

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110
Q

Mech 4: Upon binding to the their specific receptors both move into the nucleus, (unless already there), and act as ____ ______..

A

Transcription regulators

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111
Q

T or F? Some recent research however has suggested the presence of cell surface receptors for these hydrophilic molecules: this may be the reason that some produce quite short-latency responses versus affecting transcription which can take hours to days.

A

False, hydrophobic

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112
Q

T or F? Nitric Oxide (NO) and carbon monoxide (CO) have also been identified as messenger molecules.

A

True

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113
Q

Which is INCORRECT about nitric oxide?
A. The molecule who’s actions are enhanced by Viagra
B. Stimulates the production of cGMP
C. Is also strongly implicated in immune system function and synaptic transmission in learning and memory
D. Is produced by the enzyme Nitric Oxide Syntase (NOS)

A

They are all true and correct statements

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114
Q

CO appear to be involved in _____ function

A

GI

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115
Q

T or F? NO and CO are stored and are released when needed.

A

False, they freely cross membranes, they are generated on demand similarly to the steroid hormones.

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116
Q

Both NO and CO are rapidly ‘scavenged” (reduce/inactivated) therefore can only act _____

A

locally

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117
Q

T or F? Mech 4 messengers are recognize extracellular.

A

False, these messengers are membrane soluble and specific receptors are intracellular.

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118
Q

Guanylyl cyclase (GC)

A

NO and CO diffuse freelly into neighboring cells or even back into the cell that released it, they directly affect target enzymes such as ___ and possible secondary messenger production.

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119
Q

T or F? An agonist binds to a receptor and activates it.

A

True

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120
Q

T or F? An antagonist binds to a receptor but does not activate it.

A

True

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121
Q

What accessory/”extra” proteins do you need to turn off a heterotrimeric G-protein?

A

None, alpha subunits are intrinsic, containing GTPase which will turn themselves off.

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122
Q

GAP (antagonized by a GIP)

A

accessory/”extra” proteins do you need to turn off a monomeric/low molecular weight G-protein

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123
Q

T or F? A messenger molecule must be “free” to interact with a receptor:

A

False, (contact dependent messengers)

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124
Q

An activated GPR (GPCR) has how many TMD’s?

A

7

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125
Q

An activated RTK (GPCR) has how many TMD’s?

A

2

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126
Q

The action of kinases is reversed by?

A

Phosphatases

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127
Q

Phosphokinase A (PKA)

A

cAMP most important target

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128
Q

PKA has many important targets affected by

A

phosphorylation

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129
Q

Cells are subject to many different messengers from ___ to ____ and this is superimposed on the changing status of the cell itself.

A

Second ; Second

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130
Q

Adenyly Cyclase

A

What turns ATP in to cAMP

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131
Q

What turns cAMP into AMP?

A

Phosphodiesterase

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132
Q

What does PKA stand for?

A

Phosphokinase A

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133
Q

PKA is activated by _______

A

cAMP

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134
Q

When PKA phosphorates a target protein, they phosphoralate specific _____ ______ ______.

A

amino acid residues.

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135
Q

Does PKA turn on or off target proteins?

A

They can turn them on or off

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136
Q

The effects of PKA are reversed by _______

A

Phosphotase

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137
Q

What can reverse the effects of PKA?

A

phosphatases

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138
Q

What does PKA phosphorylate on the target proteins?

A

Specific AA residues

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139
Q

T or F? PKA can only turn things on?

A

False, it can either turn them on or off depending on the protein.

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140
Q

Name the targets PKA can affect.

A
  1. Active transport
  2. Channel Protein
  3. ER ( Protein synthesis, Ca2+ transport
  4. Act as transcription factor, affecting DNA transcripton
  5. Enzyme, Lipid breakdown
  6. . Enzyme, glycogen breakdown
  7. Microtubules
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141
Q

When cAMP activates PKA, then PKA activates an inactive phophorylase kinase, what is this an example of?

A

Kinase cascade

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142
Q

Can PKA enter the nucleus freely?

A

No, PKA is large, it will need to be transported in.

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143
Q

What are PLs?

A

phospholipasess

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144
Q

PLs produces different ______ _______ to mediate their effects.

A

secondary messengers

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145
Q

IP3 (Inositol triphosphate) and DAG (diacylglycerol)

A

Phosphatidylinositol biphosphate (PIP2) when cleaved by PLC and disassociates into ____ _____

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146
Q

T or F? DAG is hydrophilic.

A

False, it is hydrophobic.

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147
Q

What needs to happen before PKC is fully activated?

A

Ca2+ needs to bind with it along with DAG.

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148
Q

PLA2 will release _______ _____

A

arachidonic acid

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149
Q

If you take an NSAID, what does it block to prevent you from feeling pain.

A

Cyclooxygenase (COX1 and COX2)

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150
Q

Prostaglandins (PGs) and thromboxanes(TXs) have functions that include _____ and _____.

A

imflamation; fever

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151
Q

What do Leukotrienes affect?

A

Immune cell function (acting on leukocytes)

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152
Q

“De novo” synthesis of Sphinganine, Sphigosine, and ceramide are initiated by what enzyme?

A

Serine palmitoyltransferase (SPT)

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153
Q

Serine palmitoyltransferase (SPT) can be blocked by what?

A

SPTInhibitor

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154
Q

Name the types of sphingolipids.

A

Sphinganine, Sphingosine, Ceramide, Sphingosine 1-P

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155
Q

Fumonisins

A

mycotoxins that disrupts sphingolipid messenger functions.

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156
Q

complex sphingolipids

A

Sphinganine, Sphingosine, Ceramide can either be made by ‘De novo” or by recycling of _________ ________ in membranes.

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157
Q

If you tip the scale on the levels of sphingolipids towards Sphingosine 1-P, what will occur?

A

Anti-apoptotic, proliferation, mitogenesis, inflammation

could lead to cancer

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158
Q

If you tip the scale on the levels of sphingolipids towards ceramide, what will will occur?

A

Apoptosis, cell-cycle arrest

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159
Q

Omega-3 fatty acids are ____ __________.

A

anti-inflammatory

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160
Q

Omega-6 fatty acids are ____ __________.

A

pro-imflammatory

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161
Q

We do not make omega-3’s, if we are missing them in our diet, what are they replaced with and why is it bad.

A

Omega-6, they are pro-imflammatory

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162
Q

Ca2+ is effective on its own as 2ndary messenger, but sometimes it needs to binded with __________.

A

Calmodulin

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163
Q

What does activated MAPkkk do?

A

Initiate a kinase cascade by phosphorylating MAPkk, when then phosphorylates MAPk, which phosphorylates target proteins that affect important processess like transcription.

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164
Q

Inappropriate signaling in LMW G-protein/kinase cascade pathways can result in ________as they are so central in controlling cell growth.

A

cancer

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165
Q

apoptosis

A

Cell will undergo ______ if it is not told to survive.

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166
Q

Bcl-2

A

PI3-kinase (phosphoinositide 3-kinase) activates Akts (serine/threonine-protein kinase family) by producing PIP3 from PIP2 (DAG/IP3 pathway) by phosphorylation. PIP3 activates protein kinase 1 in turn activates Akts, which releases

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167
Q

During contact-dependent chemical messaging, the delta signal protein reaches the delta receptor of another cell, what happens to the Notch?

A

The tail is cleaved and migrates to the nucleus. Without this “growth limiting” system, cancer may result

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168
Q

Rhodopsin

A

GPR with a bound light-sensitive messenger.

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169
Q

Rhodopsin can be excited by as little as one photon and cause the activation of the heterotrimeric G-protein _______.

A

Transducin (Gt) found only in photoreceptors.

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170
Q

Adaptation: The effector is a cGMP phosphodiesterase, does it increase or decrease cGMP?

A

decreases, which in turn closes an ion channel.

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171
Q

amplification

A

Adaptation: From 1 rhodopsin to 500 transducins; 10^5 molecules of cGMP, this is an example of ___________

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172
Q

________ and ______ is a general physiological term used to describe various mechanisms necessary to cope with stimulilsignals that vary widely in strength.

A

Adaptation ; desensitization

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173
Q

__________ tends to refer more to actual changes in receptor function whereas __________ can include altered behavior

A

Desensitization ; adaptation

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174
Q

Adaptation is seen frequently in signal pathways that respond to _______ signals and ______

A

chemical ; light

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175
Q

T or F? Desensitization allows cells to respond regardless of “background” levels of stimulation.

A

False, Adaptation not desensitization

176
Q

Photoreceptors

A

can respond to a few photons on a moonless night or reduce amplification so they still respond in bright sunshine; increased intracellular Ca2+/Ca2+-dependent kinases causes this negative feedback.

177
Q

T or F? Ionotropic receptors can adapt or desensitze to repeated agonist by a “slow” confirmation change in the receptor resulting in abnormally tight binding of the agonist w/o opening the channel.

A

True

178
Q

What are the 2 principal types of receptor desensitization?

A

Heterologous and homolgous

179
Q

Homologous

A

desensitization is negative feedback within the same pathway (turning off GPR)

desensitization results in loss of G-protein coupling or removal of receptors entirely by endocytosis.

desensitization involves GRK phosphorylating the GPR which then facilitates arrestin binding which makes the GPR unable to activate its G-protein (uncoupled)

180
Q

Heterologous

A

involves negative feedback affecting GPR initiating a different pathway.

desensitization results in reduced G-protein coupling.

desensitization can trigger internalization by endocytosis, the GPR can then be degraded or recycled

181
Q

T or F? Homologous desensitization involves phosphorylation of the GPR by GRK’s.

A

True

182
Q

T or F? Homologous desensitization involves specific phosphorylation of the GPR but by different serine/threonine kinases at different serine and/or threonine residues.

A

False, Heterologous desensitization

183
Q

How is heterologous desensitization reversed?

A

By phosphatases, which restores G-protein coupling.

184
Q

T or F? Heterologous feedback mechanism often involves cAMP-dependant protein kinase (PKA) or can be PKC-mediated.

A

True

185
Q

Ligand-bound form of the GPR is phosphorylated at specific serine/threonine residues and this ________ coupling to the G-protein so it can not be activated.

A

decrease

186
Q

T or F? Arrestin binding can activate MAPK cascade by acting as an “adapter” so recruiting the various kinases to the membrane.

A

True. ( Has been most studied for teh Beta2-adrenergic receptor, its GRK is known as BetaARK and its arrestin is Beta-Arrestin)

187
Q

T or F? G-protein effector can be switch from one type of G-protien to another by being phosphorylated.

A

True. This in turn can change the response (ie switching Gs (increase cAMP) to Gi (reducing cAMP))

188
Q

T or F? GPR’s under constant agonist application will have a constant increase cell response.

A

False, there is an initial rapid decrease in response.

189
Q

T or F? Initial response to constant agonist involves no change in receptor density.

A

True

190
Q

Response to constant agonist slowly declines further due to a ______ in _____ _______

A

decrease ; receptor density (this is due to internalization)

191
Q

T or F? An agonist binds to a receptor and activates it

A

True

192
Q

T or F? an antagonist binds a receptor but does not activate it

A

True

193
Q

To turn on G-protein what is exchaged for what

A

GDP to GTP

194
Q

What accessary or extra proteins do you need to turn off a heterotrimeric G-protein

A

none

GTPase is intrinsic

195
Q

What accessary or extra proteins do you neeed to turn off a monomeric or LMW G-protein?

A

GAP (antagonized by GIP)

196
Q

T or F? A messenge molecule must be free to interact with a receptor

A

False

197
Q

An activated GPR acts as what to turn on the G-Protein?

A

GEF

198
Q

An activated GPR has how many TMD’s?

A

7

199
Q

An activated RTK has how many TDM’s?

A

2

200
Q

The action of kinase is reversed by?

A

Phophotases

201
Q

Putting a great phosphate group on molecule _________, even _____________________

A

hydrophilic; sphingolipid

202
Q

Inactive RTK? How many TMDs

A

2

203
Q

Opioid receptor unfortunately ____ or _____ effectively

A

uncopied or internalized

204
Q

Notch

A

growth limiting system malfunctions, cancer may result

205
Q

Add phospodiester (PDE) was a little mean (all other 8 were really very straight forward) you cannot hydrolyze cAMP back to AMP before you synthesize it so the addition of the PDE was irrelevant. T or F?

A

False

206
Q

PLC on PIP2. What is final product?

A

DAG and IP3

207
Q

PLA2 on PIP2. What is final product?

A

Arachidonic acid

208
Q

Function of GEP turning on RAS on. What’s happeneing on activator protein?

A

ON

209
Q

GDI antagonizes GEF. Whats happeneing to RAS?

A

OFF

210
Q

Specific Heterotrimeric G-protein pathways

A

Major signal transduction pathways affected by GPRs and heterotrimeric G-proteins and their targets.

  1. Receptor (GPRs)
  2. G-proteins
  3. Target enzymes: GC, AC, Phosphoslipase C.
  4. Second messengers: cGMP, cAMP, IP3, DAG, and AA
  5. Protein Kinases: PKG, PKA, PKC
  6. Effectors: Enzymes (transport proteins, etc.), Contractile proteins, ion channels).
211
Q

PKA

A

Protein Kinase A, which is a family of enzymes whose activity is dependent on cellular levels of cAMP (cyclic Adenosine Monophosphate)

212
Q

PKG

A

Protein Kinase G, serine/threonine-specific protein kinase that is activated by cGMP (cyclic Guanine Monophosphate)

213
Q

PKC

A

Protein Kinase C, a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins.
It is activated by DAG, (diacylglycerol).

214
Q

cAMP’s most important target

A 
Phosphokinase A (PKA), which is activated by cAMP binding to each of its 2 regulatory subunits, which then dissociate so removing their inhibition of the 2 catalytic subunits. PKA then phosphorylates its targets at specific AA residues using ATP.
PKA has many important targets affected by phosphorylation (activate or inhibit) and can be reversed by phosphatase.
215
Q

Adrenaline as a specific heterotrimeric G-protein pathways affect the sympathetic division of the autonomic nervous syste

A

Adrenaline, 1” msger binds to and activates a specific GPR (adrenergic receptor). GDP exchanges for GTP as GPR acting as a GEF on the alpha subunit (Part of Gstimulatory), so activating it and causing dissociation of the G-protein.
Alpha subunit, tethered to the membrane by a lipid tail at “right place”, activates AC which produces cAMP from ATP and then activates PKA. PKA activates glycogen phosphorylase by phosphorylation from ATP, which then causes the breakdown of glycogen and the release of glucose to fuel the response to the “fight or flight” situation.

216
Q

Translocation of activated PKA

A

PKA when activated by cAMP can also translocate to the nucleus (specifically transported), where it can affect transcription.

217
Q

Phospholipases (PLs), instead of AC, as the target.

A

Activated alpha-subunit targets and activate PL (specifically PLC in this case), instead of AC. PLC generates TWO 2ndary msgers from the membrane *Phosphatidylinositol bisphosphate (PIP2) into DAG and IP2. Inositol triphosphate (IP3) can enter cytoplasm and open Ca2+ channels in the ER causing the release of Ca2+ (which is another 2ndary msger). DAG is restricted to the membrane as it is hydrophobic: it activates PKC together with the released Ca2+.

218
Q

Types of Phospholipases PLs

A

There are many PLs which an cleave PIP2 (Phospholipid Phosphatidylinositol bisphosphate) in different places so producing different 2ndary msgers.

  1. PLD yields phophatidic acid, called PA (it’s the phosphorylated DAG), plus Inositol diphosphate.
  2. PLA2 releases arachidonic acid.
  3. PLC cleaves off similar to PLD but including the Phosphate cleavage. It only yields DAG (fatty acid and arachidonic acid) and IP3
219
Q

Effects of arachidonic acid produced by PLA2

A

PLA2 produces arachidonic acid, which is the precursor for several important msgers. Fatty acid cyclooxygenases (COX enzymes) form and then produce cyclic endoperoxides and Leukotrienes.

  1. Endoperoxides are prostaglandins (PGs) and thromboxanes (TXs)., which have many functions including inflammation and fever.
  2. Leukotrienes affect immune cell function, acting on leukocytes.
220
Q

COX has 2 forms

A

COX-1: is ubiquitous and constitutively active and thought to be required for normal cell function (homeostasis).
COX-2: is induced in cell mediating an inflammatory response when subject to the appropriate stimulus.
These enzymes are the target of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).

221
Q

De Novo (new families of lipid messengers)

A

nstead of DAG, other lipid msgers are discovered. Sphinganine, sphingosine, cermide and phosphorylated forms can be made “de novo” or recycled from complex sphingolipids in membranes (like DAG from PIP2), and have important msger functions.
“De novo” synthesis initiated by enzyme Serine Palmitoyltransferase (SPT), blocked by SPT inhibitor.

Interrelationshi

222
Q

Interrelationship between 4 of the major Sphingolipids.

A

4 major Sphingolipids mentioned above affect important cellular processes including “Apoptosis and Inflammation”. Fumonisin (mycotoxins often found in moldy corn) disrupts these pathway, affecting the relative levels of Sphingolipids and possibly trip the cell inappropriately either towards or away from apoptosis, for example.
Complex sphingolipids are important functional membrane lipids (lipid rafts), which can affect the response to certain important 1” msgers. There recycling is also affected by disruption to these pathways.

223
Q

Omega-3 fatty acids

A

Important membrane lipids that also have msger functions as anti-inflammatory. We cannot make Omega-3s (double bonds between the 3rd and 4th carbon from the opposite end to the carboxylic acid group), if missing in the diet, it’ll be replaced with Omega-6s (between 6th and 7th). ***BUT Omega-6s are pro-inflammatory.
This is a particular significance as current theories of aging, strongly indicate that the development of a chronic inflammatory condition (“Inflame-Aging”) is a major factor.
This is why elderly are often far more susceptible to disease and adverse drug interactions.

224
Q

Ca2+ as 2ndary Msger

A

Ca2+ can act as a 2ndary msger, activating certain target proteins, typically via a Ca2+-sensing intermediate such as the protein Calmodulin. Inactive Calmodulin get activated by binding multiple Ca2+ ions becoming Active Ca2+-Calmodulin (with a change in conformation), which then allows to interact with its targets.

225
Q

Where do Ca2+ come from in this pathway?

A
  1. Ca2+ can enter the cell via msger (ligand-gated), gated/opened or voltage-activated channels down its electrochemical gradient.
  2. Ca2+ can also be released from intracellular stored in Smooth ER, by the action of msgers like IP3.
226
Q

RTKs work via Kinase Cascades

A

RTKs, with or without LMW G-proteins, often exert their effects via Kinase cascades (MAPK Kinase, the most well known). Once the first member is activated (MAP Kinase Kinase), it phosphorylates and activates the next member of the cascade (MAP Kinase). Finally MAP kinase phosphorylates target proteins that affect important cellular processes like transcription.

227
Q

A typical RTK/LMW G-protein/Kinase Cascade pathway

A

The 1” msger Nerve Growth Factor (NGF) affects transcription and is anti-apoptotic. This pathway was first clarified in Drosophila (fruit fly), many techniques have been developed over the last 100 years to manipulate its genome. Inappropriate signaling in these LMW G-protein/kinase cascade pathways can result in cancer as they are so central in controlling cell growth.
*1” Msgr -> 2 RTKs activating -> Adapter proteins -> GEF (GTP on) -> Turn on Ras (also in need of PKC) -> MAPKKK -> MAPKK -> MAPK -> Rsk and/or Transcription.

228
Q

Growth factor -> Cell growth

A

Growth factors typically stimulate protein synthesis while inhibiting protein degradation/turnover. RTK is activated then trigger the activated
Phosphoinositide 3-kinase (PI 3-kinase) to further activates members of non-specific serine/threonin-protein kinase family, known as Akts.
Activated Akt releases “Bcl2”, which is anti-apoptotic and therefore promotes cell survival (Good for growing cells)

229
Q

How Atk is activated by PI 3-kinase

A

PI 3-kinase produces PIP3 from PIP2, (DAG/IP3 pathway) by phosphorylation. PIP3 then activates proteins kinase 1 which in turn phosphorylates and activates Akt.

230
Q

2 main Apoptotic pathways (figure page 11)

A

Apoptosis is essential for allowing the removal of damaged, cancerous cells.

  1. Fas ligands (death receptor) activates caspase 8 and then caspase 3 to initiate the effector stage.
  2. DNA damage activate pro-apoptotic Bcl-2 and then going through mitochondrial pathway to initiate the defector stage.
    * Effector Stage: cleavage and inactivation of enzymes and structural constituent, fragmentation of genomic DNA, etc –> Apoptosis.
231
Q

Signaling by direct contact “Notch”

A

The msger is not actually released, but cells grow and differentiate, and the actual physical contact allows interactions between captive msgers such as Delta signal protein and the Delta receptor (Notch).
After the binding, the Notch tail is cleaved and migrates to nucleus and the Notch head is still attached to the signal protein.

232
Q

Two general phases of cell cycle

A

Interphase and M Phase

233
Q

What stages are included in Interphase

A
  1. G1 (-> Go) Phase
  2. S Phase
  3. G2 Phase
234
Q
  1. G1 phase (Interphase)
A

a. Cell growth
Cell gets bigger; if not, when cell divides, it’s getting smaller and smaller when further dividing down the pathway.
b. Some cells remain in this phase for long periods of time or permanently (then go to or called Go)
Differentiated nerve and muscle cells (also heart cell) are in Go (permanently).
Liver cells normal don’t replicate unless there’s damage to it (temporarily in Go). Liver cells, therefore, can leave Go and go to G1, after it’s done with enough repairing or replacing the damage, it’ll go back to Go.

235
Q

S Phase (DNA replication)

A

a. Replication of genome (DNA synthesis)
b. DNA is copied by DNA polymerase.
c. The duplicate chromosomes remain bound together by proteins called “Cohesions” (until M-phase when the chromosomes will be separated).

236
Q

DNA polymerase

A

Replicates DNA during the S phase.

237
Q

Cohesion

A

Holds the duplicated chromosomes together after replicated (sister chromatids)

238
Q

G2 Phase

A

Cell growth after duplication.

Make sure the replication is correct and grow to be ready for division.

239
Q

What stages are included in M Phase

A

Mitosis (PPMAT)

Cytokinesis

240
Q

What phases are included in Mitosis (Nuclear division)

A

PPMAT

  1. Prophase
  2. Prometaphase
  3. Metaphase
  4. Anaphase
  5. Telophase
241
Q
  1. Prophase
A
  1. The replicated chromosomes condense
  2. Centrosomes (which replicated during S Phase) start to move to opposite sides of the nucleus and the mitotic spindle begins to assemble outside the nucleus.
    - > Centrosomes shoot out microtubules to form mitotic spindle.
242
Q
  1. Prometaphase
A
  1. Nuclear envelope breaks down
  2. This allows the spindle microtubules to contact the condensed chromosomes
  3. *The microtubules bind to kinetochores located at centromeres of sister chromatids
243
Q

Kinetochores

A

Protein complexes which assemble on the condensed chromosomes.

244
Q
  1. Metaphase
A

Mitotic spindle gathers all the chromosomes to the center (equator) of the spindle.

245
Q
  1. Anaphase
A
  1. The two sister chromatids in each replicated chromosome “synchronously” split apart
  2. Spindle draws them to opposite poles of cell
  3. Anaphase begins abruptly with the release of the linkage that hold sister chromatid together.
  4. Chromatids are pulled to the spindle pole to which it is attached.
  5. This segregates the sets of chromosomes to opposite ends of spindle.
246
Q

How APC contributes to Anaphase

A

M-Cdk (cyclic dependent-kinase) phosphorylates APC, allowing the Cdc20 bound to it, thus activating APC. Activated APC then ubiquitinates (using ubiquitin ligase) and degrades (using protease) the securin that hold separate inactive all the time. The separase then gets activated, leading tot he cleaved and dissociated cohesions (bonds holding sister chromatids) -> separated sister chromatids.

247
Q
  1. Telophase
A
  1. Nuclear envelope reassembles around each of the two sets of separated chromosomes to form two nuclei.
  2. Nucleus expands and chromosomes decondense to interphase state.
  3. Getting ready for cytokinesis by the assembly of contractile ring (at the cleavage furrow).
248
Q

Cytokinesis (Cytoplasmic division)

A
  1. Division of cytoplasm (including all organelles) by the contractile ring, which pinches the two daughter cells apart.
  2. It begins in anaphase and cytokinesis takes place quickly right at the end of telophase.
249
Q

Which enzyme replicates/copies DNA?

A

DNA polymerase

250
Q

How many chromosomes are copied? (For human)

A 
46 Chromosomes (not just the 44 autosomes).
It occurs during the S phase.
251
Q

What are the phases of mitosis?

A 
PPMAT
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
252
Q

In what phase do the sister chromatids separate?

A

Anaphase

253
Q

How does APC trigger anaphase?

A

Ubiquitinates securin by ubiquitin ligase

254
Q

Cycling-dependent kinases (CdKs) functions

A
  1. CdKs phosphorylate key proteins involved in cell cycle.
  2. It must be bound to cyclins (forming cyclin-CdK complexes) in order to be active. When cyclins are degraded by ubiquitin-proteasome system, CdK becomes inactive.
  3. A variety of CdKs and cyclins that regulate different phases of cell cycle.
  4. Aside from cyclin binding, CdKs can also regulated by phosphorylation status and CdK inhibitor proteins.
255
Q

Cyclin-CdKs for cell cycle phases

A
  1. Late G1 Phase: G1-CdK and G1/S-CdK
  2. S Phase: S-CdK
  3. M Phase: M-CdK
256
Q

Mitogens (Growth factors)

A

Extracellular signals include epidermal GF, fibroblast GF, vascular endothelial GF, platelet derived GF, neurotrophic GF, insulin-like GF, and hepatic GF.

257
Q

Quick overview of the whole process of cell cycle regulation by Cylin-CdKs

A
  1. Early G1 does not have any active cyclin-CdKs. In mammals, an external cellular signal (mitogen) is required to initiate the cell cycle (occurring in late G1).
  2. Mitogen stimulates activity of G1-CdK and G1/S-CdK which leads to the activation of S-CdK and transition into S-Phase
  3. M-CdK activity is responsible for transition through M-Phase.
  4. At the end of M-Phase/beginning of G1-Phase, all active CdKs are inactivated (waiting for mitogen to reinitiate the process).
258
Q

How does activation of G1-CdK and G1/S-CdK lead to the activation of S-CdK and entry into S-Phase?

A
  1. Activated G1-CdK and G1/S-CdK phosphorylate the Rb protein getting inactivated and releasing E2F, a regulatory protein (transcription factor)
  2. E2F is necessary to regulate the transcription genes, the cyclins including DNA polymerase, S-CdK cyclin, and other protein required for DNA synthesis and chromosome duplication, in order to transition into S-Phase.
259
Q

Do G1-CdK and G1/S-CdK activate S-CdK by phosphorylating it?

A

No, but they instead phosphorylate the RB protein, releasing the E2F that regulates the transcription genes to activate S-CdK.

260
Q

mitogen receptor

A

type RB phosphorylation

261
Q

How are G1-CdK and G1-S-CdK activated from Mitogen binding?

A

+Mitogen binds to the mitogen stimulating the Ras and MAPK pathways.
1. MAPK phosphorylates one of the gene regulatory protein, called ELK2.
2. ELK2 binds to the gene sequence expressing “myc” gene (increase myc transcription), which is a transcription factor that regulates the transcription of 3 other genes: Cyclin D, SCF subunit, and E2F genes.
I. Cyclin D gene increase the cyclin D proteins and activates the “G1-CdK.
II. Expressed SCF subunit (ubiquitin ligase) leads to the degradation of p27, which leads to the activation of “G1/S-CdK.
III. Increased E2F expression and increased release of E2F from the Rb phosphorylation leads to enhanced expression of genes required for S-Phase.

262
Q

Does MAPK activates G1-CdK and G1/S-CdK by phosphorylating them?

A

No, MAPK does not directly phosphorylate them but the ELK2 which then leads to the expression of myc gene that regulates cyclin D gene and SCF subunit to activate G1-CdK and G1/S-CdK respectively.

263
Q

What does p27 inhibit?

A

p27 inhibits G1/S-CdK. So when p27 gets degraded, G1/S-CdK get activated.

264
Q

How does cell prevent entry into S-Phase if there’s DNA damage?

A

It occurs at G1/S checkpoint.

  1. DNA damage leads to the activation of Kinases (ATM or ATR), which then phosphorylates p53 (a transcription factor).
  2. When there’s no DNA damage, p53 normally is degraded because Mdm2, a ubiquitin ligase, ubiquitinates that p53 -> p53 degradation. When p53 is phosphorylated, Mdm2 cannot bind to it and cannot ubiquitinates it.
  3. p53 increases the transcription of p21 (Cyclin-CdK inhibitor), which then binds to G1/S-CdK and S-CdK, inhibiting their activity.
265
Q

What does p21 inhibit?

A

p21 inhibits both G1/S-CdK and S-CdK preventing the initiation of S-Phase.

266
Q

Activation of M-CdK which regulates M-Phase

A
  1. M-cyclin binds to M-CdK forming the M-CdK complex.
  2. CAK and Wee-1 phosphorylate M-CdK as CAK adds an activating phosphate and Wee-1 adds an inhibitory phosphate.
  3. S-CdK phosphorylates Cdc25 (a phosphatase), which then removes the inhibitory phosphate that Wee-1 added to the M-CdK complex.
  4. M-CdK is now completely active.
267
Q

What happens to M-CdK right after activated

A

M-CdK does not only stimulate or phosphorylate APC for Anaphase, but also a lot of other functions in cell cycle such as chromosomal segregation and formation of the mitotic spindle in the metaphase.

  1. Positive feedback: M-CdK can enhance activation of more M-CdKs by phosphorylating Cdc25 becoming active, therefore, enhancing M-CdK activation.
  2. Positive feedback: M-CdK inhibits Wee-1, removing its inhibitory phosphate that Wee-1 added on.
268
Q

How does M-CdK involve both the cyclin binding and phosphorylation?

A

M-CdK become the M-CdK complex after the Cyclin binds to it. And CAK also add an activating phosphate.

269
Q

How does S-CdK activate M-CdK?

A

It does not directly active it, but it phosphorylate Cdc25, which then removes the inhibitory phosphate that Wee-1 added on -> causing the activation of M-CdK complex.

270
Q

List all the ubiquitin ligases

A
  1. APC: ubiquitinates “securin”
  2. SCF subunit: ubiquitinates “p27”
  3. Mdm2: ubiquitinates “p53”.
271
Q

List all the CdK inhibitors

A
  1. p21: inhibits “G1/S-CdK and S-CdK”
  2. p27: inhibits “G1/S-CdK
  3. Wee-1 (thought to be, but not)
    p53: not an inhibitor but a transcription factor.
272
Q

List all 4 transcription factors

A
  1. p53 -> p21
  2. ELK2 -> Myc gene
  3. Myc Gene -> three genes (Cyclin-D, SCF subunit, E2F)
  4. E2F -> S-Cdk cyclin
273
Q

What 7 genes/proteins that when mutated (inactivated) could potentially lead to excessive proliferation (enhance cell cycle)?
*Also explain how!

A
  1. Rb Protein
  2. p27
  3. Kinases (ATM or ATR)
  4. p53
  5. p21
  6. Securin
  7. Wee1
274
Q

What type of gene knock out gene loose its function to excessive cell proliferation?

A
  1. p21- inhibits cell by G1/S-CDK (normally)
  2. p53- inhibits cell cycle
  3. ATM- stimulate p53
  4. ATR
  5. Rb- inhibits E2F
  6. p27
  7. Securin
  8. WEE1- inhibits MCDK
275
Q 
P21 Inhibits:
G1/S-CDK
G1-CDK
S-CDK
M-CDK
All
Only 2 and 3
A

Only 2 and 3

276
Q 
P27 Inhibits:
G1/S-CDK
G1-CDK
S-CDK
M-CDK
All
Only 2 and 3
A

G1/S- CDK

277
Q 
How does S-CDK activates M-CDK?
In phospholyation M-CDK 
cdc25
cdc20
wee1
CAK
A

cdc 25

278
Q

MAPK actuvate G1- CDK and G1/S-CDK by phospholyation them

T or F?

A

False

myc

279
Q

G1-CDK and G1/S-CDK activate CDK by phospholyation it

T or F?

A

False

Rb phospholyates

280
Q

Two ways for cell to die

A

1: Necrosis: messy way to die, not just one cell that ends up dying but also the neighboring’s injuring them till death -> Pathology.
2. Apoptosis: very neat and quiet way for cells to die, which leads to the death of that single cell -> required to happen in the body.
50-70 billions cells die a day due to apoptosis.

281
Q
  1. Necrosis (4 points)
A
  1. Death due to injury or sever insult.
  2. Cell and organelles swell and rupture releasing intracellular contents.
  3. Induces an inflammatory response by the infiltration of immune cells (white blood cells).
  4. Damage and/or death to surrounding tissue.
282
Q
  1. Apoptosis (8 points)
A
  1. Death is tightly regulated.
  2. Cell suicide is executed via specific signaling pathways.
  3. Cells shrink instead of bursting.
  4. Condensation of nucleus.
  5. DNA fragments into oligonucleosomes.
  6. Membrane blebbing and formation of apoptotic bodies ingested by neighboring cells or macrophages.
  7. No inflammatory response like necrosis.
  8. Death of single cell (without impacting neighboring cells)
283
Q

How apoptotic bodies get ingested

A

Apoptotic bodies signal for phagocytosis, which is exposure of phosphatidylserine on outer layer of plasma membrane (like blister).

284
Q

4 Important roles of Apoptosis

A
  1. Role of apoptosis in development
  2. Role of apoptosis in health
  3. Role of apoptosis in aging
  4. Role of apoptosis in disease
285
Q

Role of apoptosis in development (2 parts)

A
  1. Webbing between digits in developing embryo (the bright green dots are the cells undergoing apoptosis)
  2. There are more nerve cells than its target cells, so the excess neurons will undergo apoptosis “in order to match the number of nerve cells to the number of target cells”.
286
Q

Role of apoptosis in health (5 parts)

A
  1. Epidermal cells migrating from the geminal layer to the surface.
  2. Epithelial lining of GI tract.
  3. Neutrophils during acute inflammatory response.
  4. Shedding of endometrium during menstruation.
  5. Killing abnormal cells that may be harmful to organism.
287
Q

Role of apoptosis in aging (5 parts)

A

Increase apoptotic potential in many cell types

  1. Loss of cardiac myocytes
  2. Loss of skeletal myocytes
  3. Loss of neurons
  4. Chondrocyte apoptosis in articular cartilage
  5. Many other tissues
288
Q

Role of apoptosis in disease (too much or too little) - 5 parts

A
  1. Neurodegenerative diseases (Alzheimer and parkinson) - Too much
  2. Ischemic Disease (myocardial infarction, stroke) - Too much
  3. Cancer - Too little
  4. Autoimmune diseases-BOTH: Too little apoptosis of immune cells which then go around the body and induce Too much apoptosis in healthy tissue cells.
  5. Many more diseases involve dys-regulation of apoptosis
289
Q

What triggers apoptosis

A
  1. Some external stimuli
  2. Internal stimuli
  3. Variations in cell type
290
Q

Some external stimuli that can trigger apoptosis

A
  1. Withdrawal of growth factors/survival signals
  2. Detachment from extracellular matrix
  3. Cytokines, produced by cells of immune system. e.g. tumor necrosis factor-alpha (TNF-alpha), FasL.
  4. Cytotoxic T cells
  5. Toxins
291
Q

Internal stimuli that can trigger apoptosis

A
  1. DNA damage

2. Mitochondrial dysfunction, characterized by decreased ATP production and excessive free radical production and damage

292
Q

Variations in cell type (nonspecific)

A
  1. Stimuli that induce apoptosis can vary between cell types (nonspecific)
  2. Resistance to apoptosis can also vary between cell types.
293
Q

Caspases: Executioners of Apoptosis

A
  1. Proteases that cleave proteins.
  2. Synthesized as proenzymes-inactive precursors.
  3. Activated by cleavage
  4. Cleavage forms large and small subunit which forms the active caspase.
  5. Caspases cleave specific substrates
294
Q

Which process is characterized by inflammatory response?

A

Necrosis

295
Q

Apoptosis is executed via specific signaling pathways.

A

True

296
Q

Are these characteristics of apoptosis or necrosis: nuclear condensation, DNA fragmentation, intracellular contacts contained within cell, membrane blebbing?

A

Apoptosis

297
Q

What happens to the apoptotic bodies that are formed?

A

Engulfed by resident macrophages or neighboring cell.

298
Q

Is the spider bite on body a necrosis or apoptosis

A

Necrosis

299
Q

Which is a necrotic liver?

A

The injured lived, indicating necrosis is not just the external injury.

300
Q

Apoptosis is involved in the development of the nervous system.

A

True

301
Q

Is cancer associated with too much or too little apoptosis?

A

Too LITTLE

302
Q

Is Alzheimer’s disease associated with too much or too little apoptosis?

A

Too MUCH

303
Q

Is Autoimmune disease associated with too much or too little apoptosis?

A

BOTH: Too little of immune cell apoptosis and too much of healthy tissue cells apoptosis.

304
Q

Which external stimulus can induce apoptosis?

A
  1. Withdrawal of growth factors
  2. Cytokines
  3. Detachment from extracellular matrix
  4. Cytotoxic T cells
  5. Various toxins
    - -> 6. All of the above
305
Q

Which are internal stimuli that can induce apoptosis?

A
  1. DNA damage
  2. Mitochondrial dysfunction
    - -> 3. All of the above
306
Q

Apotosis is involved in the development of the nervous system T or F?

A

True

307
Q

Apoptotic signaling pathways

A
  1. Intrinsic stimuli:
    a. Mitochondrial-mediated apoptosis
    b. p53 in Nuclear-mediated apoptosis
  2. Extrinsic stimuli
    a. Fas/FasL signaling
    - > Both stimulate different pathways for apoptosis, and Caspase involves in all of these pathway in some way.
308
Q

Mitochondrial-mediated apoptosis (Intrinsic); How it gets triggered:

A

Mitochondrial-mediated apoptotic signaling is activated by the mitochondrial dysfunction, caused by “Deficient ATP production” and “Oxidative stress/ROS (reactive oxygen species) production”.
DNA damage in nuclear-mediated apoptosis involves only this one pathway.

309
Q

Mitochondrial-mediated apoptosis (Intrinsic): Pathway

A
  1. When mitochondrion dysfunctions, it releases Cytochrome C, which then forms the apoptosome.
  2. Apoptosome: Procaspase-9, Apaf-1, Cytochrome C, and dATP.
  3. Activation of Caspase Cascade.
310
Q

What is Caspase Cascade?

A

When one is activated, it leads to the activation of the next one. Procaspase-9 gets activated, then being able to activate Procaspase-3.

311
Q

Activation of Caspase Cascade

A
  1. Cytochrome C, with Apaf-1 and dATP, draw Procaspase-9 together in close proximity, leading to activate itself to become (active) caspase-9. -> Called Autocleavage of Procaspase-9.
  2. Caspase-9 then cleaves and activates Procaspase-3 to be Caspase-3. -> Apoptosis occurs!
312
Q

Auto cleavage of Procaspase-9:

A

Multiple procaspase-9 come together in close proximity and cleaves each other -> activated. It then has the ability to cleave the procaspase-3.

313
Q

Types of Caspases

A

Caspases are proteases which cleave other proteins.

  1. Caspase-9: Initiator Caspase.
  2. Caspase-3: Executioner Caspase.
  3. Caspase-8: Also an initiator caspase. Needed in receptor-mediated apoptosis.
314
Q

The end results that activated Caspase-3 leads to

A
  1. Destruction of cytoskeleton
  2. Destruction of nuclear envelope
  3. DNA fragmentation into mono- and oligonucleosomes
  4. Destruction/inactivation of pro-survival regulatory protein.
  5. Membrane blebbing
  6. Formation of apoptotic bodies
  7. Apoptotic bodies engulfed by macrophages or neighboring cells, recognized by flipflop of phosphatidylserine to outer membrane.
315
Q

Regulators of Apoptosis at the Mitochondrial-mediated apoptosis (Intrinsic)

A
  1. Bcl-2 family (Family proteins, functioning as a regulation to release cytochrome-c).
  2. Inhibitors of Apoptosis Proteins (IAPs) in the cytosol.
  3. Repressors of IAPs
316
Q

Bcl-2 family proteins

A

It includes “Anti-apoptosis” and “Pro-apoptosis”.

  1. Anti-apoptotic: prevents cytochrome c release. E.g. Bcl-2 (and Bcl-Xl)-> Inhibits Bax from releasing Cytochrome C.
  2. Pro-apoptotic: favors cytochrome c release. E.g. Bax, tBid(truncated Bid) (also Bim, Bad, Bok, etc) directly release cytochrome c if it does not get inhibited by Bcl-2.
317
Q

Inhibitors of Apoptosis Proteins (IAPs)

A

This family proteins include XIAP, (and cIAP1, cIAP2, survivin).
It (mostly XIAP) binds to cleaved caspase (active) and inhibits activity of caspase-9 and caspase-3.

318
Q

Repressors of IAPs

A

These include Smac/Diablo and Omi/Htra2, released from mitochondria upon stimulation. They reside inside mitochondrion just like the cytochrome c, and when cytochrone-c is released, Smac/Diablo and Omi/Htra2 also come along to bind to IAPs and repress their inhibition on Caspases-9 and -3, allowing caspases to continue it pathway toward executing apoptosis.

319
Q

Cancer cells on Apoptosis

A

Cancer cells also overexpresses the Bcl-2 (preventing Cyto-c) and IAPs (inhibiting both Caspases), making apoptosis less likely to occur.

320
Q

How does XIAP inhibit apoptosis?

A

It binds to caspase-9 and caspase-3 to inhibit their activity.

321
Q

How does Bcl-2 inhibit apoptosis?

A

It inhibits Bax oligomerization and cytochrome c release.

322
Q

Smac/Diablo is an anti-apoptotic protein.

A

False. It inhibits the XIAP (anti-apoptotic protein), leading to apoptosis occurrence.

323
Q

What happens to Caspase-3 after getting activated?

A

Caspase-3 triggers the process of DNA fragmentation into mono- and oligonucleosomes.
In cells that don’t undergo apoptosis, ICAD binds to CAD and inhibits its activity. But when cells are undergoing apoptosis, activated caspase-3 cleaves and inactivates ICAD. Therefore, CAD then is free and active to fragment DNA into mono- and oligonucleosomes.

324
Q

What are the proteins that caspase-3 inactivates by cleavage?

A
  1. ICAD (inhibitor of Caspase-Activated DNase): cleavage of ICAD will activate Caspase-Activated DNase and lead to fragmentation of DNA.
  2. Cleavage of proteins involved in DNA repair.
  3. Cytoskeleton: will lead to cell shrinkage and membrane blebbing.
  4. Anti-apoptotic Bcl-2 family proteins.
  5. Others…etc.
325
Q

How does DNA damage lead to the accumulation of p53?

A

DNA damage activates kinases (ATM or ATR), which phosphorylates p53, making Mdm2 unable to unbiquitinate p53, leading to p53 activation.

326
Q

How does p53 halt in cell cycle?

A

p53 is a transcription factor, expressing gene p21 (inhibitor protein), which then inhibit G1/S-Cdk and S-Cdk.

327
Q

Apoptosis via nuclear signaling (p53) and its functions

A
  1. DNA damage leads to an increase or accumulation of p53.
  2. p53 has several functions:
    a. p53 halts the cell cycle.
    b. p53 plays a role in stimulating DNA repair.
    c. p53 induce translocation of Bax to mitochondria resulting in cytochrome c release.
    d. p53 also alter transcription of pro-apoptotic and anti-apoptotic protein..
328
Q

How does p53 alter transcription?

A

It alters transcription of pro-apoptotic (p53 will lead this to increase of transcription) and anti-apoptotic (p53 leads this to decrease of transcription gene).

  1. Transcriptional activation: Bax, Fas, Apaf-1, etc.
  2. Transcriptional repression: Bcl-2, Bcl-Xl, survivin, etc.
329
Q

Pathways of apoptosis “Receptor-mediated apoptosis

A

FasL or TNF-alpha binds to the receptor (Fas) leading to the activation of Caspase-8.

  1. Caspase-8 will cleave and activate tBid (truncate Bid), which then also activating Bax. thus leading to the release of cytochrome C. Then cytochrome C (with other apoptosome) creates the auto cleavage, activating Caspase-9 -> activate Caspase-3 -> Apoptosis.
  2. Caspase-8 will directly activate Caspase-3 -> apoptosis (like a shortcut).
330
Q

Two types of apoptosis in Immune system

A
  1. Direct immune-mediated killing of end-organ cells during inflammation.
    a. Cytotoxic T cell expresses FasL (Fas ligand) in its surface.
    b. Target cell expresses Fas (receptor) on its surface.
    c. FasL on cytotoxic T cell binds Fas receptor on target cell and induces apoptosis.
  2. Termination of an immune response by the induction of apoptosis (Activation-Induced cell death).
    a. Two T cells come in close proximity, each having one FasL which binds on each other’s Fas receptor, leading to the apoptosis of both T cells.
331
Q

Fas/FasL signaling detail that leads to apoptosis

A
  1. Death receptor (Fas) bind ligand.
  2. Receptors from homotrimeric complexes and the cytoplasmic tails recruit adaptor protein (FADD; Fas Associated Death Domain protein), which from intracellular side, binds to the Fas receptor embedded in the membrane.
  3. FADD recruits procaspase-8, inducing self cleavage and activation.
  4. Caspase-8 -> Caspse3 -> Apoptosis.
  5. Caspase-8 can also activate mitochondrial-mediated signaling (amplification of apoptotic signal) by cleaving Bid, then activates Bax to induce cytochrome c release from mitochondria.
  6. cFLIP interferes the recruit of caspase-8 and inhibits activation of caspase-8.
    Caspase-8 can lead to apoptosis only if there’s no cFLIP around.
332
Q

Death Induction Signaling Complex (DISC)

A

It is a complex when FADD (the DD portion) binds to the Fas receptor from intracellular membrane side, triggering the activation of Caspase-8 and binding together as complex.

333
Q

Why in some cell types, is there have to be the activation of tBid through the mitochondrion to lead to apoptosis?

A

Because it needs to release the Smac/Diablo and Omi/HtrA2 in order to prevent the XIAP from binding and inhibiting Caspase-9 and Caspase-3.
So without mitochondrial pathway and if XIAP happens to inhibit the Caspase-3, there won’t be apoptosis.
But some cells don’t need that mitochondrial pathway such as lymphocyte because it doesn’t express much XIAP.
Cancer cell over expresses XIAP (too little apoptosis).

334
Q

If you decrease the expression of Fas receptor (or none), could it undergo apoptosis via FasL, receptor mediated pathway?

A

No, because without Fas receptor, FADD has nothing to bind to, not be able to trigger Caspase-8 –> No apoptosis.

335
Q

Could that same cell undergo apoptosis in response to mitochondrial dysfunction?

A

Yes, mitochondrial pathway is intrinsic, and it can use Bax to release the cytochrome c without the help of tBid.

336
Q

What factors that helps Bax translocation to the mitochondrion?

A
  1. tBid
  2. p53
  3. Mitochondrion dysfunction
337
Q

What 5 proteins, it you increase its expression, could increase the resistance to apoptosis?

A
  1. ICAD
  2. cFLIP
  3. Anti-apoptotic proteins (Bcl-2)
  4. IAPs
  5. Mdm2
338
Q

What proteins, if you decrease its expression, could increase the resistance to apoptosis?

A

Everything to induce apoptosis.

339
Q

Over 50% of cancer has mutation of p53 (p53 loses its function). Which one of these pathways can be affected?

A

Affect BOTH pathways:
1. It reduces the expression of Bax and Apaf-1, affecting mitochondrial pathway.
2. It reduces the expression of Fas receptor, affecting Receptor-mediated pathway.
Review the function of p53

340
Q

How does Caspase 3 cause DNA fragmentation?

A

Caspase cleaves ICAD

341
Q

What if P53 mutated? Could cell undergo apotosis?

A

no

342
Q

What leads to mitocondria medicated apotisis

A
  1. mitochondria dysfunction
  2. dna damage
  3. tbid
343
Q

What kind of proteins cleave and inactivate anti apototic?

A

bcl-2 and XIAP

344
Q

tbid stimlate what?

A

translocation BAX to fold pore

345
Q

mitocondrial mediated pathway amplify apotosis, not all the time but some cell types it requires activation of tbid to undergo apotosis. why would that be?

A

some cell have high level of XIAP, bind caspase 9 and 3 and inhibit apotosis. If there is no XIAP, it caspase 9 and 3 will still work but no XIAP so aptosis will still happen

346
Q

If you decrease the expression of Fas receptor (or none), could it undergo apoptosis via FasL, DNA damage?

A

yes

347
Q

if you knock out P53, what apototic pathways will be affected?

A

nuclear mediated
mitochondrial dysfunction
receptor mediated

348
Q

4 General Characteristics of Cancer

A
  1. Cancer cells reproduce in defiance (refusal to obey) of normal restraints and invade other tissues or territories normally reserved for other cells.
  2. Majority of cancers initiated by genetic aberration (apart from normal) (mutation).
  3. Several mutations are required to cause cancer.
  4. Broad classification according to cell type from which they arise.
349
Q

Broad classification according to cell type from which they arise:

A
  1. Carcinomas -> epithelial cells
  2. Sarcomas -> connective and muscle cells
  3. Leukemias -> hemopoietic cells
    Each of these broad categories has many subdivisions according to specific cell type, location, and structure of tumor.
350
Q
  1. Benign
A

Tumors that are self-limiting in their growth and not invasive

351
Q
  1. Malignant
A

Tending to infiltrate, metastasize and terminate fatally (very invasive)

352
Q

Metastasis

A

The development of secondary malignant growths at a distance from a primary site of cancer.

353
Q
  1. transformation
A

To change from benign to malignant

354
Q
  1. Oncogene
A

A mutated proto-oncogene usually involved with controlling cell proliferation (rapid increase in number) -> induce cancer cell.

355
Q
  1. Proto-oncogene
A

Normal gene that can be converted into a cancer promoting oncogene by mutation (Wild type of non-mutated cell or a non-mutated form of oncogene).

356
Q
  1. Activation
A

Conversion of proto-oncogene to oncogene.

357
Q
  1. Tumor suppressor gene
A
  1. Gene that normally functions to suppress tumorigenesis.
  2. Loss of function mutation enhances susceptibility to cancer.
  3. Need loss of function of both alleles.
358
Q
  1. Karyotype
A

Chromosomal characteristics of a cell.

359
Q

Evolution of a tumor cell

A
  1. Most cancers arise from a single abnormal cell.
  2. Abnormality or genetic defect gives replicative advantage over other cells by following rules of mutation and natural selection that govern evolution.
  3. As advantaged cell divides, another mutation may occur giving even more advantage for survival and proliferation.
  4. Offspring of a well-adapted cell will divide the fastest eventually taking over the tumor becoming the dominant clone in developing tumor.
  5. This process takes many years to develop a progeny (descendant) of cells that have the number and appropriate mutations that make it a malignant cancer.
360
Q

Dangerous Cell Proliferation

A

The bottom picture is malignant, which has the ability to invade other underlying cells and can travel to the blood supply and get to other cells in the body that blood supplies.

361
Q

Genetic instability refers to:

A

The increasing frequency of mutational events in a tumor cells genome.

362
Q

A loss of function mutation in which gene would contribute to genetic instability?

A

p53

363
Q

A gain of function mutation in which gene would contribute to evasion (avoid, decrease) of apoptosis?

A

Bcl-2

364
Q

What are the seven Hallmarks of cancer?

A
  1. Genetic instability
  2. Sustaining proliferative signaling
  3. Evading growth suppressors
  4. Evasion of apoptosis
  5. Limitless replicative potential
  6. Sustained angiogenesis
  7. Tissue invasion and metastasis
365
Q
  1. Genetic instability.
A

DNA acquires mutations at a faster rather than normal.

  1. Defective DNA repair systems or inability to maintain integrity of chromosomes.
  2. Caused from mutation in some gene responsible for genomic stability such as defective DNA repair enzymes and defective p53.
  3. Contributes to cancer progression.
  4. Allows for more rapid accumulation of mutations.
366
Q
  1. Sustaining proliferative signaling
A

Cells are stimulated to divide when it’s not supposed to divide.

  1. Increase in number of Growth Factor (GF) receptors (RTKs)
  2. Mutant receptors that transmit signals without GF
  3. Mutations in signaling proteins that are normally activated by GF receptors (Ras, Raf)
367
Q
  1. Evading growth suppressors
A

Evading from “Cell stops dividing when it’s supposed to be dividing still”.

  1. Mutations in tumor suppressor genes such as p53 and Rb.
  2. Cell cycle not halted when supposed to be halted.
368
Q
  1. Evasion of apoptosis
A

Cell does not undergo apoptosis when it is supposed to.

  1. Increased expression of anti-apoptotic proteins such as Bcl-2, XIAP, and cFLIP.
  2. Decreased expression of pro-apoptotic proteins such as p53, Fas, etc.
369
Q

Function of Telomere and how it contribute to division/replication.

A
  1. Telomeres are sequences at the ends of chromosomes that contain no genes. It gets shorten every time a cell divide until a certain point that the cell has to stop divide because telomere is too short (usually after 50-70 cell division). Then, the cell is considered Senescent.
  2. Stem cells and immune cells express telomerase, which maintains the length of the telomeres so they don’t get shorten. Hence, they don’t lose ability to divide and do not experience “cellular senescent”.
370
Q
  1. Limitless replicative potential
A

Replicative immortality-cancer cell can divide as many times as it wants.

  • Cancer cells reactivate telomerase (90% of all tumors does):
    1. So, cancer cells can divide an unlimited number of times (replicative immortality)
    2. The 10% that do not reactivate telomere find an alternative pathway to maintain telomere length.
371
Q
  1. Sustained angiogenesis
A

Maintaining the development of new blood vessel.

  1. Cancer cells secrete high levels of angiogenic molecules inducing hypervascularization of the tumor (supply).
  2. Balance between pro- and anti-angiogenic signals is disturbed.
  3. VEGF as the most potent stimulus of angiogenesis.
372
Q
  1. Tissue invasion and metastasis
A

The development of secondary malignant growths at a distance from a primary site of cancer.

  1. Gain of function mutations in key genes which are central in cell motility (like malignant can invade other cell faster, more motile).
  2. Disruption in adhesive mechanisms that keep cells tethered together (so it doesn’t stick to where it beyond, able to leave and invade wherever it wants).
  3. Gives cancer lethal (sufficient to cause death) characteristic.
373
Q

Tumor suppressor genes require a mutation in both alleles in order for it to contribute to cancer progression.

A

True.
Gain of function mutation oncogenes require mutation in only one allele to contribute to cancer but loss function mutation oncogene require loss of both alleles.

374
Q

Nondisjunction refers to:

A

Loss of a chromosome due to failure of sister chromatids to separate.

375
Q

What type of mutation does p53 require?

A

Loss of function.

376
Q

General classes of mutation

A
  1. Gain of function mutations

2. Loss of function mutations

377
Q
  1. Gain of function mutations
A

A mutation that causes an increase in the activity or amount of a protein. Oncogene requires a gain of function and requires mutation in only one allele to contribute to causing cancer.

378
Q
  1. Loss of function mutations
A

A mutation that causes a decrease in the activity or amount of a specific protein.
Tumor suppressor genes (p53, Rb, BRCA1) require loss of function mutations and the loss of both alleles to contribute to causing cancer.

379
Q

Types of genetic mutations:

Point of mutations

A

Change of one base pair

380
Q

Deletions

A

Removal of one or more base pairs

381
Q

Insertions

A

Addition of one or more base pairs

382
Q

Translocations

A

Part of gene recombines with other genes.
A piece of genes from one chromosomes and a piece from another chromosome swap place.

ex) bcr-abl

383
Q

Amplifications

A

Extra copies of particular genes.

ex) HER-2

384
Q

Nondisjunction

A

Failure of sister chromatid to separate. One daughter cell will lose a chromosome while the other will gain a chromosome.

385
Q

7 examples of specific mutations commonly found in cancers

A
  1. p53
  2. Indirect inactivation of p53
  3. c-Myc
  4. Expression of Bcr-Abl fusion protein in chronic myelogenous leukemia
  5. Overexpression of HER-2 in breast cancer
  6. BRCA1
  7. Overexpression of Bcl-2 in B-cell lymphoma.
386
Q
  1. p53: various mutations in p53 gene render p53 inactive
A

p53 leads to activation of p21 thus inhibiting G1/S-Cdk and S-Cdk (by ATM/ATR and leaving Mdm2) halting cell cycle; p53 also translocates Bax to mitochondria releasing cytochrome c leading to apoptosis.
Mutation of p53 reduce apoptosis and increase proliferation, presenting in more than 50% of cancer cells.

387
Q
  1. Indirect inactivation of p53
A
  1. Mutation in Mdm2: gaining function of Mdm2 will degrade more p53, keep p53 level really low.
  2. Mutation in ATM: losing function of ATM decreases the phosphorylation of p53.
    Both lead to proliferation.
388
Q

What type of mutation does Mdm2 require?

A

Gain of function mutation of Mdm2 contribute to cancer by more p53 degradation.

389
Q

What type of mutation does ATM require?

A

Loss of function mutation of ATM -> less p53 phosphorylation.

390
Q

PRIMA

A

Change in conformational shape of p53, so it works even though it’s mutated.

391
Q

RITA

A

To prevent the Mdm2 from binding to p53 even if Mdm2 is accumulated.

392
Q

Would RITA be effective at treating cancer in a mutation of p53?

A

No, even though RITA interfere with p53 degradation from Mdm2, the p53 that is accumulated are mutated, so it doesn’t work anyway.
If you coming RITA and PRIMA, it could be used to treat cancer.

393
Q

What type of mutation does Myc require?

A

Gain of function mutation of Myc lead to more activation of G1-cdk and G1/S-Cdk, leading for increased cell cycle (proliferation).

394
Q
  1. c-Myc: various mutation in c-Myc gene lead to gain of function
A

Mutations lead to over expression of the gene or produces a hyperactive protein. This mutation is found in a large percentage of cancers:

  1. 90% of Burkitt’s lymphoma patient
  2. 80% of breast cancers
  3. 70 % of colon cancers
  4. 90% of gynecological cancers
395
Q

What type of mutation does Abl require?

A

Gain of function mutation.

396
Q

What type of mutation produces Bcr-Abl?

A

Translocation

397
Q
  1. Expression of Bcr-Abl fusion protein in chronic myelogenous leukemia (CML)
A
  1. It is due to translocation event forming Philadelphia chromosome (95% of CML patient have this mutation).
  2. Bcr fragment makes it hyperactive which leads to excessive WBC’s.
  3. Bcr-Abl is a hyperactive protein tyrosine kinase that can activate PI-3 kinase and Ras.
  4. Treatment strategy for CML is Gleevec.
398
Q

How Gleevec is used to treat chronic myelogenous leukemia (CML)?

A

Gleevec sits in ATP-binding pocket of tyrosine kinase domain and prevents transfer of Phosphate from ATP to substrate protein, so there’s no signal for cell proliferation and survival for leukemia.

399
Q

What type of mutation does HER-2 require?

A

Gain of function mutation.

HER-2 is a RTK that growth factor binds to in order to lead to proliferation.

400
Q

Why type of mutation cause over expression of HER-2?

A

Amplification.

401
Q
  1. Overexpression of HER-2 in aggressive breast cancer.
A

Over expression of HER-2 is postulated to result in the formation of homodimers resulting in a constitutively active receptor, which leads to the amplification of gene. It occurs in about 25% of breast cancer patients.
Herception is a monoclonal antibody that blocks the receptor site and leads to destruction of receptors from immune system. (Vaccine against HER-2 is in development).

402
Q

What type of mutation does BRCA require?

A

Loss of function mutation to contribute to cause cancer.

BRCA is one of the tumor suppressor genes.

403
Q
  1. BRCA1 (Breast Cancer type 1)
A

It is Breast Cancer Type 1 susceptibility protein that inhibits cell cycle and stimulates DNA repair (like other tumor suppressors).
Hundreds of mutations have been identified in this gene.

404
Q

BRCA genetic testing

A

It determines if an individual has inherited a mutation in one allele of the BRCA1 gene.
(Very high of cancer chance because you only have one simple allele and if that one is also get mutated, it’ll cause cancer)
IF inherited mutation in one allele, 80% risk of developing breast cancer and 50% risk of getting ovarian cancer. Some women decide to remove their breast and ovary to prevent this if positive BRCA test.

405
Q

What type of mutation does Bcl-2 require?

A

Gain of function mutation.

406
Q
  1. Over expression of Bcl-2 in B-cell lymphoma
A

The over-expression of Bcl-2 is due to translocation, which Bcl-2 can end up being next to the enhancer.
Cancer cells will become resistant to apoptosis (as Bcl-2 inhibit Bax from releasing cytochrome c).

407
Q

Treatment strategy

A

Antisense therapy targets mRNA.
After gene transcribing Bcl-2 makes Bcl-2 mRNA, it will be interrupted by Bcl-2 antisense through the process of RNase-H, and the Bcl-2 mRNA gets degraded, lowering the bcl-2 level.
Bcl-2 mRNA doesn’t get even translated.

408
Q

Difficulties in treating cancer

A

Different types of cancer or even two different tumors of the same kind of cancer have different genetic mutations. -> Need to target different gene.
Different therapies might target different level of gene expression (different step of the gene transcription/translation).

409
Q

most maliganant cells contain a single mutation.

t or f?

A

false

410
Q

mutation in Rb protein then what hallmarks?

A

evading growth supressors

411
Q

what is genetic instability?

A

the increasing frequency of mutational events in a tumor cell genome

412
Q

tumor cell acquire to start evasion? (3)

A
  1. down regulation and decrease adhesion expression of neighboring cell.
  2. secretion of MMP
  3. Gain of fucntion in motality gene
413
Q

what kinds of cell express telomerase?

A

stem cells, immune cells, germ cells

414
Q

what type of mutation does myc require?

A

gain of function

415
Q

what kind of mutation ABL require?

A

gain of function

416
Q

what kind of mutation mdm2 require?

A

gain of function

417
Q

what type of mutation p53 require?

A

loss of function

418
Q

would rita affect treating a cancer that has loss of function in p53?

A

no prevent mdm2 binds, accumulating p53 however dysfunction due to loss

419
Q

would rita affect treating a cancer that has gain of function in p53?

A

no contributing cancer

420
Q

what type of mutation does ATM OR ATR require?

A

loss of function

421
Q

what type of mutation produces BCR-ABL?

A

translocation

422
Q

what type of mutation would require HER-2

A

gain of function

423
Q

what type of mutation causes over expression of HER-2?

A

Amplification

424
Q

what type of mutation does BRCA require?

A

loss of function

425
Q

what type of mutation BCL-2 require?

A

gain fo function

426
Q

antisense technology targets?
dna
mrna
protein

A

mrna

427
Q

Angiogenesis

A

Development of new blood vessel.

  1. Small tumors can receive adequate O2 and nutrient by diffusion from blood vessel.
  2. Large tumors need growth of new blood vessels.
  3. Onset of angiogenesis is due to the imbalance between pro- and anti-angiogenic factors (upregulation of pro-angiogenic proteins/downregulation of anti-angiogenic protein).
  4. Normal vasculature is quiescent in healthy adults with each endothelial cell dividing once in every 10 years. Adult, active angiogenesis is required only for wound healing, endometrial proliferation, and during pregnancy.
428
Q

What’s the most potent stimulus for angiogenesis and how?

A

VEGF (Vascular Endothelial Growth Factor)

  1. Hypoxia, the most potent stimulus for expression of angiogenic factors (VEGF) production by tumor. Hypoxia-inducible transcription factor (HIF) binds to VEGF gene and induces transcription of VEGF -> new blood vessels.
  2. Mutation in p53 results in overexpression of VEGF.
  3. Activation of Ras can also lead to overexpression to VEGF.
429
Q

Process of Angiogenesis

A
  1. Pericytes are cells related to vascular smooth muscle, which are located adjacent to and surround the endothelium. They detaches, and blood vessels dilate.
  2. Basement membrane and extracellular matrix degraded by matrix metalloproteinase (MMPs).
  3. Endothelial cells migrate into perivascular space toward angiogenic stimuli (VEGF) produced by tumor cells.
  4. Endothelial cells proliferate.
  5. Endothelial cells adhere to each other and create a lumen.
  6. Formation of basement membrane and pericyte attachment.
430
Q

Endothelial survival factors/receptors

A

Make proliferation of angiogenesis by binding to angiogenic factors leading to tube formation supplying blood into tumor cells.

431
Q

Treatment of tumor

A

It’s believed that treating tumor is to target the blood vessels that are supplied to that tumor -> target different cells that recruit those new blood vessels formation.
Targeting the VEGF pathway

432
Q

Targeting the VEGF pathway

A
  1. Soluble VEGF receptors binds to the VEGFR-2.

2. Anti-VEGF antibodies bind to the VEGFR-1.

433
Q

What are Invasion and Metastasis?

A
  1. Invasion is the migration of cells into deeper tissues - cancer cells break through the barrier that keeps them localized.
  2. The invasive phenotype is what categorizes a tumor as malignant.
  3. Metastasis is the spread of cancer cells from a primary tumor to distant sites in the body.
  4. Invasiveness and metastasis are the major cause of treatment failure.
434
Q

8 Steps in Metastasis

A
  1. Tumorigenesis- primary tumor growing, need mutation
  2. Angiogenic switch- more secretion of VEGE and less secretion of VEGER
  3. Acquire invasive phenotype- If successful, need three characteristics to start tumor cell. (3)
  4. Survival in circulation
  5. Tumor cell arrest
  6. Extravasation & growth at secondary site
  7. Angiogenesis in secondary tumor
  8. Evasion of immune response
435
Q

What are the 3 needs for a tumor cell to acquire invasive phenotype?

A
  1. Changes within the cell that down regulates the adhesive molecules. If not, they stay attached and don’t get to the neighbor cells.
  2. Secretions of MMP (matrix metalloproteinase), eventually from a passive way to the blood vessel. MMP breaks the basal membrane to let the tumor cells get into the blood stream.
  3. Turn on motility system. It can crawl to the nearby cell, down the blood stream.
436
Q

Immune Privilege

A

Tumor cells can avoid death by cytotoxic T cells and induce apoptosis of T cells.

  1. Immune cells (cytotoxic T cells) express FasL kill the ones that express Fas receptor.
  2. Tumor cells express Fas L (normal cells usually do not) and down regulate Fas receptor.
  3. Tumor cells can up regulate cFLIP
  4. Both 2&3 lead to tumor cells (with low Fas) resistant to apoptosis by cytotoxic T cells; and tumor cells (due to FasL expression) induce apoptosis in cytotoxic T cells.
437
Q

Viruses and cancer

A

Viruses play a role in cancer.
Human papilloma virus (HPV) has hundred types but only a few of them can cause cancer, which two of them are E6 and E7.
1. E6 will bind and inhibit p53.
2. E7 will bind and inhibit Rb protein

P1 (12 decks)

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