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Chapter 10 Flashcards

1
Q

What does each phase represent;
G1 phase?
G1 restriction point?
S phase?
G2 phase?
M phase?
G0 phase?

A

G1; quiescent stage
G1r; Major cell cycle pause, once passed it is a point of no return
S; DNA Synthesis
G2; quiescent phase
M; mitosis
G0; permanent arrest of G1 in cardiomyocytes

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2
Q

What are tyrosine/kinases, and what is their role in cardiomyocytes?

A

These are CDKs which control the cell cycle progression. These are important in foetal and developing tissue, and those under proliferative signaling (eg hypertrophic cardiomyopathy)

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3
Q

How do CDK’s function?

A

CDK has to pair with a cyclin to become PARTIALLY activated. CDK+cyclin become fully activated phosphorylated by a CDK activating kinase (CAK) (using ATP)

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4
Q

How does a cardiomyocyte exit the G1 restriction point?

A

CDK4 binds cyclin, which releases transcription factor E2F from an inhibitory complex with a retinoblastoma protein

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5
Q

What are retinoblastoma proteins?

A

“pocket proteins”, which are tumour suppressor proteins. E2F transcription factors bind into the pocket of retinoblastoma (RB) proteins

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6
Q

How do retinoblastoma proteins control cell cycling?

A

E2F is bound in the pocket of RB. HYPO phosphorylation of pRB binds to E2F inactivating it. However, HYPERphosporilation of serine/threonine residues causes pRB to eject and activate E2F, a transcription factor, which causes the cell to transition through the G1 restriction point

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7
Q

Are genes active or dormant in cardiomyocytes?

A

Dormant

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8
Q

In 9 points, describe transcription and translation

A

1) RNA polymerase + transcription factors bind to DNA promotor
2) DNA helicase unwinds DNA
3) RNA polymerase passes over unwound DNA and produces primary RNA transcript
4) Exons are arranged and spliced from the RNA
5) tRNA transports spliced exons out of the nucleus into the cytoplasm (mRNA)
6) mRNA is methylated and ribosomes translate
7) mRNA degraded
8) post transcription protein activation and deactivation occurs
9) proteolysis

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9
Q

What is TATA box?

A

promotor region (thymidine, adenine alternating) weakpoint where DNA is most easily unwound by helicase

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10
Q

What is a DNA promotor and repressor site?

A

These are sites transcription factors bind to. Promotors upregulate gene transcription, repressors the opposite.

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11
Q

How to hormones regulate gene transcription?

A

They are fat soluble and diffuse through the cell and nuclear membrane, where they bind to nuclear receptors which act as promoters for gene expression

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12
Q

What are telomerers ?

A

DNA ends made of TTAGGG sequences and proteins called shelterin’s that protect the DNA from enzyme degradation

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13
Q

What is alternative splicing?

A

Introns are eliminated alternatively and exons scrambled to make different proteins

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14
Q

What is epigenic regulation ?

A

This is NON-mendelian inherited genetic changes secondary to proliferative signalling. This affects phenotype without depending directly on the DNA base sequence - this is what allows diet, neutering, substance abuse etc to modify gene expression

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15
Q

What are the 3 mechanisms involved in epigenetic control?

A

1) Direct DNA changes by mobile genetic elements (DNA retroviruses, plasmids etc), covalent modification (by cytokines or chemicals [egsmoking etc]), and interaction between TRANS-gene alleles
2) RNAi (i=interference) which inhibits RNA translation
3) Post-translation modification of Histones - alters the ability of DNA to interact with transcription factors

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16
Q

What are miRNA’s?

A

There are interferance RNA’s which regulate maladaptive responses such as myogenesis, cardiac development, and proliferative responses

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17
Q

What is DICER and where does it originate?

A

DICER is an endonuclease made from miRNA’s synthesised from the drosha (non-protein encoding) region. DICER cleaves out short RNA regions which bind to proteins to form RISC (RNA-induced silencing complex)

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18
Q

What are nucleosomes?

A

Chromosome stabilisers are made of DNA wrapped around histone cores. The Histones make DNA inaccessible to transcription factors.

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19
Q

What are HATs?

A

Histone Acetyl-Transferase, this exposes proliferative signaling sites on the DNA

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20
Q

What are HDACS?

A

Histone DeACetyl-Transferases which condenses DNA into chromatin making it innacessible

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21
Q

How are HDACS inhibited in cardiac hypertrophy ?

A

HDACS are phosphorylated by CAMkinase (calcium-Calmodulin Kinase) and PKC (Protein Kinase C), inhibiting their ability to condense DNA into chromatin (which makes it inaccessible to transcription factors). This allows proliferative signals to be transcribed.

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22
Q

What are growth factors?

A

There are extracellular signals which involved in proliferative signaling (cytokines are the other important type)

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23
Q

What is the nomenclature of peptide growth factors and examples?

A

Named after the tissue they were discovered in. IGF, insulin like growth fact; VGEF, vascular endothelial growth factor etc

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24
Q

What are the mechanisms used by growth factors to bind to their receptors and activate signalling?

A

1) Ligand-receptor; Growth factor binds a recptor activating protein kinases or other enzymes that activate intracellular signalling
2) GF binds receptor resulting in the formation of multi-protein aggregates which have a docking scaffold which binds to additional intracellular signaling molecules

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25
Make a table which shows the extracellular signal, receptor, couple proteins, second messenger or mediator system and intracellular targets for proliferative signalling;
26
When are fibroblast growth factors activated
Participate in the healing response to injury or when there is pressure overload where they cause hypertrophy
27
Decribe the FGF (fibroblast growth factor cascade)?
Fibroblast growth factors bind to a transmembrane tyrosine kinase. This phosphorylates TRK, leading to detachment of intracellular signal S, and causes a group of intracellular signals (S1->S5) to activate a transduction pathway which leads to proliferation
28
how does the RAAS affect FGF cascade?
Angiotensin II releases FGF, endothelin and other mediators of the haemodynamic defence mechanism which have proliferative functions
29
why is transforming growth factor beta (TGFβ) activated, and what does it do ?
This is a proliferative response to injury and it downregulates fibroblast proliferation but upregulates the synthesis of matrix proteins
30
What is the role of TGFβ in the foetus?
It stimulates myogenesis and myocyte differentiation
31
How does TGFβ differ from FGF in its proliferative effect?
FGF promotes fibroblast deposiotion, which TGFβ results in matrix protein deposition in sites of injury or stress
32
What does the activation of TGFβ result in in the adult heart?
Eccentric hypertropy from matrix protein deposition, upregulation of foetal genes and apoptosis
33
How does RAAS affect TGFβ?
Angiotensin II upregulates a mediator of TGFβ called SMAD3. SMAD3 upregulates TGFβ resulting in fibrosis, maladaptive hypertrophy etc
34
Describe the structure and activation of TGFβ receptors ?
Type I and II made of serine/theorine subunits. TGFβ binds to type II which results in the phosphorylation of type I. Type I phosphorylation in phosphorylation of SMAD3, SMURF, TAK1 etc which kick off another cascade affecting DNA transcription.
35
How do cytokines signal within the cell?
They do not interact directly with tyrosine kinases but they interact with other membrane proteins which contain tyrosine kinases
36
Examples of cytokines?
Interferons, TGFβ, TNFα, erythropoietin, Granulocyte colony-stimulating growth factor and thousands more
37
What beneficial roles do cytokines have? What detrimental roles do cytokines have?
- promote cell repair and healing, promote inflammatioon - promote inflammation, hypertrophy to overload,
38
What controbutes to cahexia?
High levels of circulating TNFα
39
TNFα, in what life stage is this expressed?
Foetal and it should not be expressed in adults. It is only expressed in adults when there is stress and overload on the heart
40
How specific are cytokines and their receptors?
Cytokine receptors are specific to one type of cytokine, but cytokines can bind to more receptors
41
Give a general overview of how cytokine receptors work?
Cytokines bind to transmembrane receptors, which form intracellular aggregates of coupling units (eg gp130). Downstream we see phosphorylation of tyrosine, less so threonine and serine.
42
What is JAK-STAT and how does it work?
One of the most important signaling cascades. JAK is bound by cytokines/growth factors, where it phosphorylates STAT. STAT dissasociates from JAK and moves into the nucleus where it regulates transcription
43
What do they stand for and what do SOCS and PIAS stand for?
SOCS; suppressor of cytokine signalling PIAS; protein inhibitor of stat These are inhibitors that prevent STAT. These are nuclear phosphorylases which turn off DNA binding motifs p300, CREB-binding-protein and CR6-interacting-factor 1 (CRIF1) via the dephosphorylation of STATS.
44
What other signalling pathways can cytokines use?
Cytokines can bind to the Death Domain on MAP-kinases (mitogen-activated-protein-kinases), activating NF-κB. NF-κB, via proteasomal degradation of ubiquitin, allows for NF-κB to detach and then be transferred to the nucleus, where it transcribes DNA.
45
What is cytokine shedding?
This is proteolysis of cytokine receptors which dislodges them from the cell wall rendering them soluble.
46
What are the most common ligands for GPCR (G-protein Coupled Receptors) which allow for proliferative signalling?
Endothelin, Angiotensin II, β-adrenergic agonists, vasopressin, sphingosine-1-phosphate
47
Draw a diagram of heterotrimeric GPCR pathways involved in proliferative signaling?
48
What are the roles of monomeric GPCRs, and give examples of ligands? Examples of GPCR monomeric units?
These are molecular switches or timers. There require GTP dephosphorylation to activate and a ligand such as the following; RAS, RHO/RAC, CDC42, RAB, ARF, SAR1 and RAN. Examples of monomeric subunit are Gαq, Gα12/13, Gαs and Gαi.
49
What determines the length of time a monomeric G protein is active for?
The rate of GTP hydrolysis and the rate at which GDP is replaced by GTP.
50
Why do Monomeric G-protein signals persist for longer than heterotrimeric ones ?
BEcause the rate of GTP hydrolysis is higher in the trimeric receptors.
51
What proteins can affect the length of monomeric GPCR signaling?
GAPs (GTPase activating proteins) activate GTPases which shorten the signal, and GEF (guanine nucleotide exchange factor) which increases the rate of GDP exchange for GTP.
52
What other mechanisms can change the rate of monomeric GPCR signalling?
Cytoskeletal deformation, post-translational modifications such as methylation, palmitoylation, phosphorylation, glutathionylation and farnesylation.
53
How do statins work?
They attenuate Rac and Rho (GPCR) signaling
54
what cytosolic receptors are involved with proliferative signaling?
Protein kinase C Calcium calmodulin domain protein kinases Calcinerin HDACs histone deacetylases
55
What is the role of calcinerin ?
This is a phosphatase which is bound by calcium and dephosphorylates the inactive form of transcription factor NFAT (nuclear factor of activated T cells) which activates GATA and MEF2C factors resulting in cardiac hypertrophy
56
What form do phospholipase C receptors come in?
- Classical; which requires both DAG and Ca for activation - Novel; requires DAG but not Ca - Atypical; which requires intracellular messengers derived from lipids.
57
What are the 3 components of Mitogen-Activated protein kinases pathways?
1) upstream; MAP Kinase kinase kinase 2) Midstream; Map Kinase Kinase 3) Downstream; Map Kinase
58
How are MAP receptors activated and what do they do?
Involved in proliferative signaling that causes cell growth (and proliferation) which results in hypertrophy. Stresss activates Map Kinases, cytokines, GPCRs, cytoskeletal deformation and many others.
59
Explain how heterotrimeric GPCR affect cell proliferation via MAP-kianses?
H-GPCR are bound by ligands such as Angiotensin II, Nerepinepherine, endothelin, and other functional signalling pathways. These GPCRs result in the production of InsP3-induced Ca2+ release and activation of PKC pathways. The PKC pathways meidcate cell proliferation messenger signaling and are inoled in prolonged sympathetic proliferation
60
What are ERKs
Extracellular receptor kinase - these are the extracellular receptors which initiate the ERK -> Signal+P -> GRB2->SOS-> RAS -> MPKKK->MPKK->MPK-> Transcription factor cascade. ERKS autophosphorylate when bound by a ligand which results in the formation of a docking site for the signal that kiks off the cascade to bind to and become phosphorylated
61
what is ERK1/2 activated by?
Cytoskeletal deformation
62
What are examples of stress-activated MAPK pathways in addition to ERKs? how do these work?
P38 and JNK ( c-Jun aminoterminal kinases ) TGFβ, ASK, Raf-1 etc.
63
What is the role of PIP3
Recptor tyrosine kinases which are bound by a ligand can result in the phosphorylation of PIP3 by PIP3Kinase. This subsequently phosphorylates AKT which upregulates mTOR, GSK3 and FoxO. This whole path is known as a MAPkinase like pathway
64
What is the role of mTOR?
Mammalian target of rimfamycin - inhibits one or both of GSK3 or FoxO. This also controls protein synthesis rate, nutritional status, gene expression, and coordinates cell growth.
65
What is the role of GSK3?
Regulates glycogen metabolism and participates in proliferative signaling. GSK3 provokes apoptosis and inhibits several maladaptive transcriptions to overload including NFAT, β-catenin and GATA4
66
What is the role of FoxO ?
Involved in cardiac development. However, in adults, activations favour atrophy and reduced cardiomyocyte size
67
What happens to mTOR in energy-starved hearts?
Results in a decrease in [ATP]/[ADP] ratio which activates MAP kinase that reduces mTOR activation by PIP3-AKE which can lead to adaptive and maladaptive responses.
68
What are the ways in which the cells die?
1) extrinsic factors - necrosis or oncosis 2) intrinsic factors - apoptosis or autophagy
69
What are hallmarks of necrosis?
cell swelling, breakdown of the plasma membrane, rupture of cell contents, inflammatory response, fibrosis
70
What are hallmarks of apoptosis?
cell shrinkage, phagocytes, phagocyte engulfed fragments
71
Why is necrosis detrimental to the heart tissue?
Cardiomyocytes are not replaced but rather replaced with fibrosis affecting contractile function. Additionally, the large release of Ca2+ allows for a surge in myofilament exposure which can result in explosive contracture, further damaging surrounding cells
72
How does necrosis progress within a cell?
Usually reversible in the early stage and results due to an increase in permeability of the cell membrane that leads to cell swelling. This is followed by the formation of plasma membrane blebs which rupture spilling their contents into the cytosol. The contents of the cell result in inflammation and further necrosis.
73
How is apoptosis initiated and progress?
Proliferative or other signals (eg injury) induce cell shrinkage. The plasma membrane will eventually break up and surround fragments of cell material (apoptotic bodies- contain chromatin, ie DNA). This prevents a massive inflammatory response
74
Where is apoptosis an essential yet beneficial role in the heart?
During cardiac development as cells of no further use have to make way for newly developing ones.These unneded cells cannot be allowed to fibrose.
75
What are the two main ways in which apoptosis is triggered?
1) molecular signaling; G-protein receptor antagonists, growth factors, cytokines etc 2) initiated by damaged mitochondria within the cells.
76
What is the death receptor pathway?
Fas2 ligand binds to plasma membrane mFasL and soluble sFasL receptors. There is a 70-90aa sequence in the Fas receptors called "death domain" which binds to adaptor proteins such as FADD (Fass-associated death domain protein) which forms a death-inducing signal complex that activates cytosolic proteins called FLIP (Fas ligand inhibitory protein).
77
How do the mitochondria cause death ?
Controlled by members of the BCL2 peptide family (B-cell lymphoma/leukaemia 2 gene) which include both pro and anti apoptotic pathways. These can promote cell death or prevent it via several pathways. Cytochorme C exits the mitochondria into the cytosol and binds to prolapsase-9 and APAF1 (apoptotic protease activity 1) . This forms an austosome that inactivate Caspase-9 and procaise-9.
78
What is the role of caspases in the cell?
Caspases hydrolyse cytoskeletal and nuclear regulatory proteins, tumour supressors, and enzymes that participate in RNA splicing, cell division, DNA repair and replication.
79
what is p53
Master watchman protein which regulates cell cycling. in proliferation tissue, p53 has a pro-apoptotic effect which prevents uncontrolled proliferation.
80
What are the two steps in myocardial response to stress?
1st gene to be upregulated - immediate in early response genes - that are not normally transcribed in G0. These are activated within minutes by phosphorylation. There are 100's activated at various times 2nd gene to be upregulated - late response genes - these are activated by transcription factors where synthesis is stimulated by the early genes.
81
Examples of early response genes?
c-fos, c-jun and c-myc
82
What is hypoxia-inducible factor (HIF) ?
HIF-α1, found in the heart, increases the synthesis of proteins that protect against hypoxic damage. This upregulates erythropoietin, VEGF (promotes blood vessel formation), metabolic enzymes which increase anaerobic ATP production, signaling, and molecules that inhibit apoptosis
83
What are heat shock proteins?
These minimise damage to cells by stabilising their hydrophobic surfaces that become exposed to denatured proteins. These are amongtsh the first to be actiabted by stress.
84
Give two examples of proliferative pathways activated by Angiotensin II
H-GPCR bound by angiotensin II result in production of InsP3 which induces Ca release and activation of PKC pathways. PKC mediate cell proliferation, messenger signaling and are involved in prolonged sympathetic proliferation. Angiotensin II upregulates a mediator of TGF-beta called SMAD3. SMAD3 upregulates TGF-beta resulting in fibrosis, maladaptive hypertrophy etc
85
What is this an example of an why
Necrosis; we have fibrosis, inflammation, cellular contents disposed of through the matrix, and extravascular RBC's
86
What is this an example of and why?
This is apoptosis. You can see cell shrinkage, small encapsulated chromatin bodies, there is no significant inflammation or fibrous deposit and there is no contamination of the tissue with extracellular contents
87
what are the endocrine mediators of maladaptive response? What are the mechanical mediators of maladaptive response? What are the mitochondrial mediators of maladaptive response?
88
what happens when you have ATP deprivation
pumps do not function-> lactic acid production-> Atp inbalance
89
where can calcium go to be buffered
mitochondria sarcoplasm cytoplasm

Katz (6 decks)

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