Exam 3 Flashcards
What isotope indicates how old tissues are?
Carbon 14
What is Apoptosis
programmed cell death
Does apoptosis cause damage to tissue?
No
What cleans up cells which have undergone apoptosis?
Macrophages
True of False?
Intracellular constituents are released into extracellular milieu durring apoptosis.
False
What causes necrosis?
severe cell damage
What does necrosis lead to or present as?
Inflimation
What happens to the intracellular contents during necrosis?
The are released into the extracellulara milieu
How does apoptosis contribute to embryonic development?
Removes cells to sculpt the body
What causes a frog to loose its tail?
Induced apoptosis in the tail
What common disease is apoptosis important for protecting against?
uncontrolled cell division, cancer
What is the function of apoptosis generally?
serve as a safety system for removing cells which have lost normal comunication and control
What is the function of apoptosis in neuronal development?
it matches the number of developing nerve cells to the number of target cells
how do target cells match the correct number of nerve cells?
By releasing a limited amount of survival factor which prevents apoptosis of nerve cells
what morphology changes occur during apoptosis?
mild convolution
chromatin compaction and margination
condensation of cytoplasm
breakup of nuclear envelope
nuclear fragmentation
blebbing
cell fragmentation
True of False?
Asymmetric lypid distribution is maintained during apoptosis.
False
the negatively charged lipid phosphatidylserine (PS), which is usually only found on the inner side of the membrane, is exposed to the extracellular side of the membrane
what does phosphatidylserine (PS) do when exposed to the extracellular space?
signals macrophages to phagocytose the cell
what do restriction enzymes do?
they cut DNA at specific sites
How does agarose gel from gel electrophoresis seperate DNA?
size with the largest particles nearest to the well
What is the negative side of agarose gel in gel electrophoresis?
the well side
what is the DNA stain used at the end of agarose gel electrophoresis?
what is needed to visualize the stained DNA?
ethidium bromide
UV-light
What does necrosis do to DNA on agarose gel electrophoresis?
creates a DNA smear
What does apoptosis do with regards to DNA?
activates nucleases which cut the DNA between the nucleosomes
What executes apoptosis?
caspases
what are caspases?
proteases
what activates procaspases?
their prodomains are cleaved off
what do activated procaspases do?
dimerize to form on caspase molecule
what will one molecule of active initiatior caspase do?
activate many executioner caspase Y
What does executioner caspase y do?
cleave the nuclear lamin and activate many more executioner caspase Z
what does executioner caspase Z do?
cleaves cytosolic proteins
How does the initiator caspase get activated?
the aggregation of procaspases
what helps the procaspases agregate?
adaptor proteins
What do agregated procaspases do to each other and what is the result?
cleave each other resulting in the formation of active caspase
True of False?
The active initiator caspase can cleave and activate many executioner caspases
True
how many different caspases do human cells express?
15
what is released from the mitochondria that initiates the apoptic pathway?
cytochrome C
where is cytochrome C stored in the mitochondria?
intermembrane space
What does cytochrome C bind to and activate in the apoptic pathway?
What do those activated things subsequently bind to?
adaptor proteins
other adaptor proteins
What are cyclized adaptor proteins called?
apoptosome
How does p53 activate apoptosis
it acitvates the Bax transport protein which releases Cytochrome C into the cytoplasm
What cells contain the fas ligand?
killer lymphocytes
what doe the fas ligand bind to?
the fas receptor
What happens once the fas lignad binds the fas receptor?
A DISC is fromed which initiates apoptosis
What is a DISC?
the fas receptor bound to adaptor proteins which are bound on the other end to procaspase molecules
Describe how a virus infected cell gets delt with.
Virus infected cells present viral peptides at the cell surgace (antigen)
T Cell Receptors (TCR) recognize the antigen
this causes the fas ligand to bind the fas receptor and initiate apoptosis
How does the DISC initiate cell apoptosis?
By activating procaspases and helping them dimerize.
What are C. elegans?
Nematodes (round worms).
What are doomed cells?
cells that are genetically programmed to always undergoe apoptosis in the lifecylce of a multicellular organism
How many doomed cells were identified in C. elegans?
131
What are the CED-3 and CED-4 genes required for?
apoptosis
What is the function of CED-9?
suppress apoptosis
What is the vertebrate analog to C. elegans CED-9, CED-4, and CED-3?
Bcl-2, Apaf-1, and Casp9
Vertebrates require an aditional step to initate cell death when compared to C. elegans. What is it?
Casp9 needs to activate Casp3 in vertebrates
C. elegans undergo cell death after CED-3 (the Casp9 analog) is activated
What are the different stem cell types and how are the different?
Embryonic (pluripotent) stem cells
Adult (somatic) stem cells
somatic maintain a specific tissue while pluripotent differentiate into various tissue types
Where do pluripotent stem cells come from?
the blastocyst
True of False?
C. elegans have somatic stem cell lines for most of their tissue types?
False
the only somatic stem cell lines in C. elegans are the germ line stem cells (GSCs)
What are the vili?
specialized epithelial areas of the gut that absorb nutrients
True of False?
The vili have a high turnover rate and must constantly be replaced.
True
Where do find vili?
Mammalian intestines
What is the tip of the vili called?
Villus
What is the basal cavity of a vili called?
the crypt
What is the function of goblet cells in the vili?
mucus secretion
Where are new cells made for the vili?
at the bottom of the crypt
where are old cells recycled in the vili?
at the villus
How long does it take a new cell in the crypt to navigate to the villus?
3 to 6 days
How is the crypt structured?
The very bottom are dividing stem cells
middle half is dividing precursor cells (non-differentiated)
top portion is non-dividing, differentiated cells
What are the cells types at the very bottom of the crypt in villi?
dividing stem cells
non-dividing terminally differentiated Paneth cells
True of False?
Cells continue to divide in the villus?
false
What are the two cell types of the villus?
secratory cells
absorbative cells
Where are skin cells born?
The bottom of the epidermis
What happens to newly replicated skin cells?
They differentiate into keratin containing cells, die, and finally shed
What is the major layer below the epidermis?
The dermis
What sepperates the dermis from the epidermis?
The Basal Lamina
Define Tissues.
Tissues are groups of cells that act together to perform a specific function
What are groups of cells that perform specific functions called?
Tissues
What are gap junctions?
Transmembrane proteins that link the cytoplasm of neighboring cells
What is allowed to flow through gap junctions?
ions and small molecules.
Describe the morphology of gap junctions.
Six subunits cyclize to form a nm channel.
These macrounits are called connexons
Two connexons from different cells connect to form a gap junction.
The space between cells with gap junctions is 2-4 nm.
What are desmosomes?
Protein complexes that form strong physical connections between cells.
Describe the morphology of desmosomes.
Keratin filaments bind to cytoplasmic plaque.
Cytoplasmic plaque binds to transmembrane cadherin proteins.
Cadherin proteins of differnet cells interact to bind the cells together.
What is the cytoplasmic plaque made of?
intracellular linker proteins
In reference to the Extra Cellular Matrix (ECM) what facilitates a strong network between cells?
Secreted proteins and polysaccharides.
True or False?
Integrin links the cell to the collagen of the ECM?
True
Where is integrin found?
The plasma membrane
What is vitamin C deficiency commonly known as and what does it do?
Scurvy
It weakens connective tissues (loss of ECM)
What is proline?
An amino acid.
What is hydroxylation?
The addition of an alcohol (hydroxyl) group
What hydroxylizes proline?
What does this enzyme require as a co-factor?
procollagen-proline dioxygenase
vitamin C (ascorbate)
What is the Ascorbate also known as?
Vitamin C
What is vitamin C also known as?
Ascorbate
Describe the morphology of collagen fibers.
Amino acid chains containing proline fold into a-helical chains.
Three a-helical cahins form a collagen molecule.
Many collagne molecule form a collagen fibril (like rope).
Many fibrils form a collagen fiber (like a bigger rope).
True or False?
There are many distinct epithelial systems disconnected from one another.
False
There are many epithelial systems but they are all connected.
Describe the various functions of epithelial cells.
protection, secretion, absorption, excretion, filtration, diffusion, and sensory reception.
Describe where epithelial cells can be found.
All body surfaces, lining of cavities and hollow organs, and glands.
What is the major cell type found in glands?
epithelial
What is the general category of disease caused by aging?
Name three specific examples.
damage-based diseases
cancer, diabetes, and alxheimer’s
How does aging affect telomeres?
Aging reduces telomere length.
How does aging affect dividing cells?
Aging causes a loss of dividng cells (stem cells).
About how many times can stem cells divide?
Aproximately 50
What things accumulate with aging?
damaged cells and molecules as well as mutations in nuclear and mitochondrial DNA.
True or False?
Researchers originally thought yeast were immortal.
True
How many times can yeast divide before going into senescence?
about 25 to 30 times
What is senescence?
G zero phase of the cell cycle
What is the replicative lifespan of yeast?
The time when yeast are actively replicating
What is the chronological lifespan of yeast?
Aproximately how long is the chronological lifespan in yeast?
The survival of non-replicative yeast.
weeks to months
True or False?
90% (aprox.) of a cells DNA and proteins are dedicated to regulation.
True, maybe
Babst made up the number
True or False?
There is a corilation between complexity of organism and genes dedicated to regulation.
True
more complex = more regulation genes
Name some cellular programs.
cell differentiation, cell cycle initiation, celly cycle exiting, apoptosis
True or False?
Each step from brith to death of a protein can be regulated
True
and it usually is regulated
What does each type of regulation require?
A certain time to respond to a signal
What types of things are controlled via regulatory processes?
transcription, enzyme activity, protein stability, protein localization, cellular programs, RNA processing, mRNA transport and localization, mRNA degredation, translation, etc.
Why does regulation inhibit enzymes from creating their product?
an overaccumulation of product makes product synthesis inefficient.
Where is product inhibition (enzyme regulation) used commonly?
Metabolic pathways
is feedback regulation (enzyme regulation) inhibitory or activating?
inhibitory
What is feedback regulation (enzyme regulation) mainly used for?
regulating non-reversible reactions
regulating key steps in metabolic pathways
describe feedback regulation (enzyme regulation).
A chemical affects the quantity or activity of an enzyme such that the chemicals synthesis is blocked. I.e. a chemical blocks a reaction upstream in the pathway that led to its synthesis.
True or False?
Chemicals can only block one step/reaction in a cellular pathway (feedback regulation).
False
What is aspartate transcarbamoylase?
What does it do?
An enzyme involved in the synthesis of the nucleotides CTP,UTP, and TTP
How does aspartate transcarbamoylase (asp-t) get regulated?
What kind of regulation is this?
A downstream product of asp-t, CTP, binds the regulatory site of asp-t and inactivates.
feedback regulation
What does CTP bind and inactivate?
aspertate transcarbamoylase
When CTP bind aspertate transcarbamoylase what is CTP functioning as?
a regulatory ligand
What do kinases do?
phosphorylate things
What is phosphorylation?
The addition of a phosphate group to something via covalent bond
Describe how covalent modifications can regulate proteins.
The presence of a phosphate group covalently bound to a protein can activate or inactivate the protein.
What do phosphotases do?
remove phosphate groups from proteins
What does acetylation do to lysine?
removes the posative charge by adding an acetyl group to the amine
R-NH3+ to R-NH-Acetyl
True or False?
Ubiquitination is a form of protein regulation.
True
it is a form of regulation via covalent modification
True or False?
p53 has a relatively simple regulation system.
False
it hase many phosphorylation, acetylation, and ubiquitination sites
True or False?
p53 acts as a coincidence detector.
True
How does localization regulate proteins?
The presence of certain bound molecule affects the functionality of a protein.
Think when GTP is bound protein equals ON
When GDP is bound protein equals OFF
Describe how Sar1 is an example of protein regualtion via localization.
When Sar1 is bound to GDP it is inactivated and soluable
When the GDP is swapped for GTP by an exchange factor (GEF ) a hydrophobic tail is esposed on Sar1 allowing it to bind to a membrane
What does active, anchored Sar1 do?
initiates vesicle formation
What is an alternative name for protein regulation via assembly?
protein complex formation
What does the assembly of coat proteins and cargo receptors do?
drives vesicle formation
What are Sec23 and Sec24?
coat proteins
What form of regulation controls Actin and why?
assembly/disassembly and localization
the presence of ATP vs ADP changes what actin subunits can do. the synthesis or degredation of AF is what drives the functionality of AF
What are the different types of protein regulation via proteins synthesis?
Regulation of transcription
Regulation of mRNA processing
Regulation of mRNA nuclear export
Regulation of mRNA stability
Regulation of translation
What are transcription factors?
DNA binding proteins that regualte transcription initiation
What are the two domains of transcription factors?
DNA binding domains and transcription regualtory domains
True or False?
Most transcription factors are monomers but some are dimers.
False
most are dimers
What do homeodomains do?
form hydrogen bonds with nucleobases
Where do homeodomains locate themselves when binding to nucleobases?
Mostly the major groove of DNA
True or False?
Homeodomain-DNA interactions are specific for certain DNA sequences.
True
What are homeodomains important for?
development in multicellular organisms
What are homeodomains?
The parts of transcription factors which bind to the DNA
What do homeodomain transcription factors do to increase specificity?
function together with other transcription factors
How do leucine zipper transcription factors interact?
They form dimers
Describe the leucine zipper transcription factor complex structure when bound to DNA.
Two a-helix cross and from an x shape reffered to as the leucine zipper. one groove of the x stratles DNA and the two legs bind the DNA on opposite sides
True or False?
Yeast are an example of simple eukaryotes.
True
what is the promoter region of a gene?
the region upstream of a transcription start site where transcription factors bind the DNA
What is an enhancer region of a gene?
a binding site for transcriptional activator proteins
Where are enhancer regions of genes located?
They can be upstream or downstream of the transcriptional start site
In what type of eukaryote can transcriptional acitvators act far away from the transcription start site?
higher eukaryotes (more complex)
True or False?
Many transcription factors act together to regulate transcription.
True
How specific are transcription factor binding sites?
not that specific
What is the mediator complex?
a protein complex that interacts with several transcription factors to regulate transcription initiation
How do transcription repressors do their job?
Physically compteing with activating transcription factors for DNA binding sites or suppressing transcription via the mediator complex
What is a transcription factor?
DNA binding protein that affects transcription initiation
How are transcription activators and repressors different?
activators increase transcription of a gene while repressors decrease transcription
what is an enhancer?
DNA sequence that is recognized by a transcription activator
what is a silencer?
DNA sequence that is recognized by a transcription repressor
True or False?
Trancription activators and repressors are what we call transcription factors.
True
Describe the promoter region.
DNA region usually upstream of the transcription start site with enhancer/silencer sequences and importantly an RNA polymerase binding site.
What are the three states of the gal promoter?
repressed, de-repressed, and active
What keeps the gal promoter repressed?
the presence of glucose
In the absence of glucose and galactose what blocks the Gal4 activator?
Gal80
What condition are needed for the total activation of Gal4?
How does this activation work
The presence of galactose and absence of glucose
the absence of glucose removes downstream inhibitory proteins
galactose then binds Gal3.
Gal3 binds to Gal80
Gal80 in turn unbinds Gal4 thus activating it.
True or False?
Some transcription factors can affect the expression of hundreds of target genes.
True
Describe how transcription factors affect cell identity.
Several transcription factors which control complex gene expression programs can lead to changes in gene expression patterns.
Name the types of protein regulation covered.
feedback regulation
covalent modification regulation
localization regulation
assembly regualtion
synthesis regulation
Which type of protein regulation has sub categories of regulation?
synthesis regulation
How can trasncription factors influence transcription initiation through recruitment?
By recruiting histone modefying enzymes or chromatin remodeling proteins
What is the consequence of histone acetylation?
It can help recruit transcription factors to the promoter region.
How do chromatin remodeling proteins affect transcription?
They can increase access to trasnscriptional start sites
What are epigenetics?
Heritable changes in gene function/activity that are not changes in DNA sequence
What form do epigenetics mostly present as?
Changes in transcription
**
What is the memory effect?
Epigenetic mechanism involved in cell fate determination and other long term changes in cell populations
How clear is it that epigenetic changes propogate to daughter cells?
future generations of individuals?
clear (well known)
less clear
What are the two major mechanisms of epigenetic changes?
histone modification
DNA methylation
What is the enzyme group that does DNA methylation?
methyltransferases
What gets methylated in DNA methylation?
cytosine
What does DNA methylation do?
suppresses gene expression by recruiting/attracting transcription repressors
True or False?
DNA methylation is forgotten by the second generation of following daughter cells.
False
The methylation pattern is maintained by daughter cells
What does epigenetic histone modification do?
Changes the access to promoter regions
True or False?
Histone modification can be inherited by the daughter cells.
True
How are histones modifications different in the gametes?
in humans
They are mostly erased
What is most of the genome dedicated to in higher eukaryotes?
regulatory RNA molecules (rRNA)
What is the function of micro-RNAs (miRNA)?
trigger the degredation of mRNA or reduce their translation efficiency
What is the function of small-interfering RNAs (siRNA)
they protect cells from foreign RNA
What is a function of long non-coding RNAs?
regulation of gene expression
What are the regulatory RNAs?
miRNA
siRNA
Describe how miRNA leads to the degredation of mRNA.
Precursor miRNA is processed to form miRNA
single strand miRNA gets bound by RISC protien(RNA-induced silencing complex)
miRNA -RISC complex binds mRNA and the mRNA is degraded
Besides mRNA degredation how do miRNAs affect gene expression?
interfering with translation
What are siRNAs made of?
What binds a mature siRNA?
cleaved foreign RNA
RISC protein
What do researchers use siRNAs for?
silence expression of a specific gene
What is Gcn2?
a kinase
What is elF2?
a Translation initiation factor
What activates and thus causes Gcn2 to phosphorylate elF2?
uncharged t-RNA
What does phosphorylated elF2 do?
blocks the guanidine-exchange factor (GEF) elF2B
What does elF2B do?
activates elF2 by exchanging the GDP for GTP
What does Gcn2 do in the big picture and why?
starvation conditions activate Gcn2 which blocks general translation.
What is an example of protein regulation via protein degredation?
cyclins getting degraded at specific times in the cell cycle
p53 getting degraded constantly unless damaged DNA is detected
True or False?
Many cell surface proteins get inactivated by endocytosis.
True
What is the general way in which cell signaling works?
extracellular signal is sensed, signal gets sent inside the cell, and protein regulation changes as a result.
What are the basic types of cell communication?
Contact dependent (cell-cell contact)
synaptic (directed)
paracrine (short distance)
endocrine (long distance)
Autocrine (self signaling)
gap junctions (cell connection)
describe paracrine signaling.
signal A changes gene expression in neighboring cells resulting in secretion of signal B. Signal B induces changes in gene expression of neighbor cell which equals differentiation.
True or False?
The cummulation of multiple signals is what tells the cell what to do.
True
What do signaling scaffolds do?
increase speed, efficiency, and specificity of signal transduction
What are the two types of signaling scaffolds?
preformed and post-activated
what is the general structure of signaling scaffolds?
intracellular protein which binds on one end to a receptor protein
along the length of the scaffold other inracellular signaling proteins bind in order
How does receptor down regulation work?
Why is this process important?
a signal molecule and its bound receptor is endocytosed and degraded in the lysosome
This process adjusts sensitivity to a signal (it can turn off a signal)
What is are the two basic types of receptors? Which one is more common?
cell-surface (more common) and intracellular receptors
Which signal receptor binds hydrophobic signals and which binds hydrophilic?
hydrophobic -> intracellular
hydrophilic -> cell-surface
What is signal transduction?
The process of communicating an extracellular signal to intracellular components
What do intracellular receptors typically function as?
transcriptional regulators
What are nuclear hormone receptors?
lignad-regulated transcription factors
How is signal transduction often mediated?
phosphorylation and small GTPases
What are second messengers?
small moelcule or ions that relay the signal from the plasma membrane throughout the cell including the nucleus
How are second messengers often used?
They are used for the amplification of a signal
What are three cell surface receptor families?
G protein coupled receptors
receptor tryosine kinases
notch receptor
What is the largest family of cell surface receptor proteins?
G protein coupled receptors (GPCRs)
How many GPCRs are found in humans?
How many in yeast?
over 700
3
How many transmembrane domains do GPCRs have?
7
What is the G protein of GPCRs made of?
a trimer of the alpha, beta, and gamma subunits
What G protein subunit acts like a small GTPase
the alpha subunit
What does the activated GPCR act like?
a GEF (guanedine exchange factor)
What happens once a GPCR gets activated?
It binds to a G protein complex
G alpha-GDP becomes G alpha-GTP
G alpha dissociates form G beta-gamma
What are downstream targets usually called?
effectors
G alpha-GTP does what?
interacts with effectors and triggers their activation
What does trimerization do to G alpha and G beta-gamma complexes?
turns off their signaling
What do high levels of cAMP cause?
lipolysis (breakdown of storage fat)
True or False?
Adenylyl cyclase only gets activated by G proteins .
False
G proteins can activate and deactivate adenylyl cyclase depending on the type of g protein
What are heart pacemaker cells?
neurons
how does acetylcholine affect pacemaker cells?
Acetylcholine binds a GPCR
G protein trimer gets activated and alpha subunit seperates from beta-gamma
beta-gamma subunit binds and opens a potassium channel
potassium flux hyperpolarizezs the membrane potential which makes action potential harder to form
this slows down heart reat
hydrolysis of G alpha-GTP terminates this signal
*
What is a Pl?
a phospholipd that plays an important role in cell signaling and protein trafficking
True or False?
Pls have one phosphorylation site?
False
What do the different phosphorylated versions of Pls do?
function as markers for different membranes in the cell
What do Ptdlns do?
function as specific markers for organelles
How many different binding domains do ptdlns have?
many, at least four
What is the function of Ptdlns?
localize proteins to specific organelles or to activate signaling cascades
Ptdlns4p is specific to where?
Golgi
Ptdlns4,5P2 is specific to where?
plasma membrane
Ptdlns3P is specific to where?
lysosomes
Ptdlns3,5P2 is specific to where?
lysosomes
How do Ptdlns direct trafficking?
Proteins bind the Ptdln that associates where they want to go
**
What is the result of the inositol phopholipid pathway?
activated protein kinase C (PKC)
What role does calcium2+ play in signaling?
it is a messenger
describe how calcium2+ functions as a messenger.
very little calcium is in the cytoplasm so its release has profound impacts on the cell
What is the sensitivit of human rod cells?
about five photons
How do human rod cells work?
cation channels open in the dark resulting in depolarization
this leads to constant neurotransmitter secretion
What closes the cation channels in rod cells?
light
Where are rod cells found?
The back of the retina which is the back of the eye
describe how light closes cation channels in rod cells.
light activates a GPCR which activates a G protein complex
the active A subunit acitvates a cGMP phosphodiesterase
the phosphodiesterase converts cGMP to GMP
lower cGMP means the cGMP gated channel gets closed
What is retinal?
the light sensitive co-factor in rhodopsin
What is rhodopsin?
opsin (GPCR) + retinal
How many G proteins can be activated by rhodopsin which has absorbed only one photon?
500
True or False?
One photon can casue a rod to send a signal to the brain.
True
The signal amplification system in rods can do this but typically you would want/need more photons for a signal to the brain
How can the dark signals of rods (rhodopsin by proxy) be conveyed in light situations?
Rhodopsin kinase can use ATP to phosphorylate rhodopsin
this reduces G protein Alpha subunit from being activated
if rhodpsin has been phosphorylated enough and there is still more light what happens?
arrestin can bind the phosphate groups and inactivate rhodopsin completely
What does notch receptor signaling require?
direct cell contact
When a notch receptor binds the substrate what happens?
The intracellular domain gets proteolyticaly celaved and the cleaved domain becomes a transcription activator
What do notch receptors function in?
Multicellular organism development
How many subfamilies are there of Receptor Tyrosine Kinases (RTKs)?
Seven
What is the largest class of RTK?
Eph receptor
What are the major morphological components of RTKs?
transmembrane domain
tyrosine-kinase domain (Cytosolic)
kinase insert region (Cytosolic)
Cysteine rich domain (Extracellular)
Immunoglobulin-like domain (Extracellular)
fibronectin type III like domain (Extracellular)
What is the rarest type of kinase?
Tyrosine Kinase
What is the energy source and source of phosphate for a Kinase?
ATP
What are trophic factors?
Factors that tell the cell to live
List the seven families of RTKs.
EGF receptor
insulin receptor, IFG-1 receptor
NGF receptor
PDGF receptor, M-CSF receptor
FGF receptor
VEGF receptor
Eph receptor
What activate the EGF receptor?
Epidermal growth factor (EGF)
What is EGF a potent promoter of?
cell survival, growth, and proliferation
List some facts about EGF.
53 amino acid protein
3 intramolecular disulfide bridges (Cys-Cys)
Produced by several cell types notably epithelia cells
Almost all human cells respond to EGF
What do most RTKs activate?
the small GTPase Ras
What do RTK signaling molecules usually take the form of?
protein/peptide dimers
When a signaling molecule binds RTKs what happens?
The RTKs dimerize
What does RTK dimerization do?
Activates the tyrosine kinase
What does the active tryosine kinase do?
phosphorylates the other RTK
Once the RTK has been phosphorylated what happens next?
signaling protiens are recruited to the RTK in a scaffold like manner and they relay the signal to different effectors
How does an active RTK interact with the Ras protein?
an adaptor binds the active RTK to Ras-GEF
the Ras-GEF exchanges the Ras GDP with GTP
What is the on state of the Ras protein?
GTP bound
When Ras gets activated What happens?
downstream signaling pathways are activated
Where is Ras located?
the cytosolic side of the plasma membrane
What is MAP KInase?
Mitogen Activated Protein Kinase
What acitvates MAP kinase kinase kinase?
The active Ras protein
What activates MAP kinase kinase?
What does this activate?
MAP kinase kinase kinase
MAP kinase
What does MAP kinase activate?
many proteins involved in gene expression and protein control
What kinds of signals can MAPKs interpret?
Chemical, enviromental, physical, etc.
Describe the diversity of MAPks signaling response diversity.
everything from protein regulation to osmolarity control to cell locomotion
What do we call a complex cellular response?
a cell program
True or False?
Sexual reproduction is limmited to higher order eukaryotes.
False
What is required for conjugation in yeast sexual reproduction.
think signaling
A pheromone pathway
How do scaffold proteins contribute to signaling orginization?
They seperate and arange different signaling pathways.
What receptor activates the Pl 3 kinase? What is the signal that binds this receptor?
RTKs
trophic factors
Where is Ptdlns (3,4,5)P3?
the cytosolic side of the cell membrane
What does the production of Ptdlns (3,4,5)P3 casue?
Protein kinases get recruited to the plasma membrane
What do protein kinases bind to on Ptdlns (3,4,5)P3?
the phospho domains
What does the inactive Akt kinase bind to?
the phospho domains of Ptdlns (3,4,5)P3
What is Bcl2?
An apoptosis inhibitor
What is the inactive Bcl2 protein bound to?
The Bad protein
What phosphorylates Bad (protein)?
Akt Kinase
When Bad gets phosphorylated what happens?
Bad becomes inactive
Bcl2 gets released and activated
How does p53 activate apoptosis?
through the protein Bax
what does Bax do?
release cytochrome c from the mitochondria
How does Bcl2 inhibit apoptosis?
by supressing Bax and the relase of cytochrome c
what is the function of apoptosis?
safety system to remove cells that losse normal communication and control
True or False?
when cells do not receive trophic factors they stay in the state they are in.
False
the abscense of trophic factors leads to apoptosis
What is uncontrolled cell division called?
cancer
what does Tor stand for?
Target of Rapamycin
what is Tor?
A kinase regulated by nutrient availability
How do low nutrients affect Tor?
They block Tor activity
What is the result of low Tor activity?
autophagy, blocked translation, and blocked cell cycle (starvation response)
what drug blocks Tor?
rapamycin
When injested what does rapamycin do to a cell?
induces the starvation response
What is the pharmaceutical purpose of rapamycin?
used to prevent transplant organ rejection
What activates Tor Kinase?
Akt
What does activated Tor kinase do?
inhibits protein degredation and stimulates protein synthesis
True or False?
Tor kinase acts as a coincidence detector.
True
What are coincidence detectors?
proteins that integrate many intra and extracellular signals to determine cell fate
they take all the info available and make a decision
True or False?
Signaling pathways are linear chains to definite responses.
False
lots of signaling pathways are linear but many also interconnect and the result is not always the stimulated cell program
What is the significance of receptor desensitization?
Maintaining special and temporal specificity of signal
How is the activated EGFR degraded?
rapidly via the MVB
what activates the EGFR?
EGF binding it
cellular-Cbl (c-Cbl) does what?
binds and ubiquinates activated EGFR
what is c-Cbl?
a ubiquitin ligase
how is v-Cbl differnet from c-Cbl?
v-Cbl was discovered first
v-Cbl was found in viruses
v-Cbl is shorter than c-Cbl
v-Cbl binds EGFR but does not ubiquinate it
What is a micro-consequence of v-Cbl binding EGFR?
EGFR can not be ubiquinated
What is the macro-consequence of v-Cbl being expressed in a cell?
Tumorigenesis
what is an oncogene?
a gene which can stimulate transformation of a cell into a tumor cell when expressed
True or False?
v-Cbl is a normal oncogene.
False
it is a potent oncogene
True or False?
Many oncogenes are mutated tumor suppressors.
True
Synonym for Tumorigenesis
oncogenesis
Oncogenesis meaning
cancer forming process
proto-oncogene meaning
a gene that when mutated promotes tumor formation
True or False?
Proto-oncogenes and tumor supressor genes often function in cell cylce regulation, apoptosis, and/or cell signaling.
True
What are the two defining charachteristics of cancer?
uncontrolled division
invasion into other tissues
what is the most common type of cancer?
Where does it start?
carcinomas
eptithelia cells
What is important to remember about cancer formation?
it requires an acumulation of a series of mutations
True or False?
Cancer cells maintain their identity as the travel through the organism.
False
they loose their identity
List some things required for tumorigenesis.
self-sufficient growth signaling
insensitivity to antigrowth signals
evasion of apoptosis
limitless replicative potential
tissue invasion and metastasis
sustained angiogenesis
What is angiogenesis?
The formation of new blood vessels
What things do cancer “evolution” require?
High mutation rate
high proliferation rate
TIME
How does cancer loose regulatory systems?
through genetic mutations
What are the mutations that lead to cancer?
mutations in coding regions
gene amplification
chromosome rearrangement
why is genetic background (multi generational heredity of individuals) important to cancer?
mutations can be inherited form parents
What is a dominant mutation?
What is a recessive mutation?
gaining a function
loosing a function
What is an example of cancer exhibiting genetic instability?
higher mutation rate
chromosomal translocation (peices of chromosomes getting rearranged )
Why are HeLA cells really bad for research?
The scrambled DNA changes the functionality of the cells compared to healthy cells
What causes gentic instability?
external factors (x-rays, UV, radiation, chemicals) damage DNA
Oxygen radicals made by the mito. can react with DNA
DNA replication is not perfect
Why does it make sense that most cancers are carcinomas?
they have lots of exposure and high chemical rates
What causes the rapid acumulation of mutations in cancer cells?
the loss of DNA repair systems and DNA damage check points
What percent of human cancers have mutations in p53?
50
what is p53 in terms of cancer?
a tumor suppressor
How does p53 work?
when dna damage is detected p53 is activated
p53 promotes the expresion of p21
p21 binds and inactivates Cdks thus stopping the cells cycle
Why is angiogenesis necessary for cancer?
cancer needs nutrients to survive and grow
What is the furthest any cell in the body will get away from a blood vessel?
about four cells
What are many cancer cells required to do for energy?
Why is this?
they are forced to do fermentation for ATP
they are too far way from blood vessels and thus oxygen
How do tumor cells upregulate glycolysis?
overexpression of glucose importers and glycotic enzymes
What is APC
a ubiquitin ligase
what tells cells in the crypt to proliferate
the wnt signaling pathway
What turns off the wnt signaling pathway?
degredation of the transcription factor beta-catenin
what degrades beta-catenin?
APC via ubiquitination and transport to the proteasome
What is the other name for the E3 enzyme?
APC
How can APC mutations lead to cancer?
They can lead to loss of proliferation control which could lead to cancer
What is the rate fo breast cancer for women in the US?
about 1/8
What are BRCA 1 and BRCA 2?
tumor supressor genes
When BRCA 1/2 mutate what happens?
Risk of breast cancer increases dramatically
What are BRCA 1/2 involved in?
repair of double stranded DNA breaks
DNA double stranded break (DSB) repair by recombination is good becasue why?
the repair is error free
How is DSB repair by DNA ligase differnet than by BRCA 1/2?
DNA ligase repair losses a few nucleotides near the break site
BRCA 1/2 looses no nucleotides near the repair site
How do BRCA 1/2 repair DSBs?
by processing the broken ends and using undamaged DNA as a template
True or False?
Cancer cells listen to the signals of surrounding cells?
False
What is the morphology of breast cancer cells?
amorphous cell clusters
What is metastasis?
cells of the primary tumor becoming mobile, invading other tissues, and forming secondary tumors
Tumors that stay local and do not metastasize are called what?
Benign
Tumors that metastasize are called what?
malignant
For metastasis to happen what is required?
weakening of cell-cell interactions
more specifically weakening of the ECM
what is the protein at the branching points of actin?
Arp 2/3
Describe how blebbing works.
How do cancer cells use this for movement?
The cell membrane looses contact with the cortex
turgor pressure forces the membrane out into a bubble
The blebbed portion of cell membrane sticks to a new cell and the blebbed cell pulls itself in this direction
How controlled is the movement of cancer cells?
uncontrolled and totaly random
What does adenylyl cyclase do?
Produces cAMP
What is the lipid that signals phagocytosis when exposed to the extracellular space?
phosphatidylserine (PS)
What is the learned function of phosphatidylserine (PS)?
what is PSs charge?
signal phagocytosis when exposed to the extracellular space during apoptosis
negative
What blocks aspartate trasncarbamoylase?
what kind of regulation is this?
CTP (a product of aspartate transcarbamoylase)
feedback regulation
besides interacting with the mediator complex how else can transcription factors influence transcription initiation?
by recruiting histone modefying enzymes and chromatin remodeling proteins/complex
What do histone modefying enzymes do?
acetylate histone
the acetyl group helps recruit transcription factors to the promoter region
what is the name of the enzyme that acetylates histone (lysine side chains).
acetyltransferase
How do chromatin remodeling complex affect transcription?
the physically increase access to the promoter region of a gene by spreading out nucleosomes
What are the two epigenetic mechanisms?
histone modification and DNA methylation
what enzyme methylates cytosine?
methyltransferase
what does methylated cytosine do?
recruits transcription repressors
what do general histone modifications do?
besided recruiting transcription factors.
they change access to the promoter region of a gene
What does Ptdlns stand for?
phosphoinositides
What is the abreviation for phosphatidylserine and phosphoinositides
PS and Ptdlns respeectiveyly
Describe the inositol phospholipid pathway.
a signal binds a GPCR
active GPCR acts as a GEF for a G protein
the disosiated a subunit activates a phospholigase
the phospholigase cleaves the lipip portion of ptdnls4,5p2 from the inositiol
the lipid portion anchors protein kinase C (PKC)
the 1,4,5 inositol travels to the ER and binds as a ligand to a ligand gated claium channel
calium (Ca2+) is released into the cytoplasm and binds the PKC
the PKC is now active
What is the final produc of the inositol phospholipid pathway?
protein kinase C
