Flashcards in 9-16 Cell Cycle III Deck (36):
Mitogen pathways occur in which cell cycles?
G1 Go leading into S-PHase
Explain normal activation of RTK (receptor Tyrosine Kinases) 
Receptors dimerize in response to eXtracellular ligand binding-->then 2 Tyrosine kinase domains CROSS phosphorylate each other which INC kinase domain activity------->those active kinase domains now phosphorylate other sites along the receptor=FULL ACTIVATION
1-What happens when you have a mutant RTK Tyrosine Kinase receptor?
2)What will excess levels of mutant RTK lead to?
3) How do Cell Biologist use this to their advantage?
1-Mutant RTK can dimerize normally when ligand binds BUT can NOT cross-phosphorylate a normal receptor in a dimer----->if Mutant RTK is in excess it will dimerize & BLOCK normal receptors ability to send signals= 2) DOMINANT NEGATIVE REGULATION
3) Biologist intentionally use Mutant dimer receptors to inhibit and thus determine specific functions of normal receptors or signaling protein
Once other sites on RTK are initially phosphorylated how does intracellular signaling proteins come into play?
Intracellular CYTOSOLIC signaling proteins bind to phosphorylated tyrosine's after initial activation.
------->produces that broadcast multiple signal pathways
1) What is the Grb-2 adaptor?
2) SH2 domain of Grb-2?
3) SH3 domain of Grb-2?
1( "GrabiT" adaptor with a SH2 domain and SH3 domains used to transmit downstream signals when Tyrosine sites are phosphorylated
2) SH2 domain=literally grabs a specific phosphoryltd Tyrosine site
3) SH3 domain=grabs polyproline helix of Ras-GEF activating its ability to convert Ras-GDP-->Active Ras-GTP
What happens when Ras-GEF is activated by _____
When polyproline helix of Ras-GEF is bound/activated by SH3 domain of Grb-2 it converts Ras-GDP--->Ras-GTP which then later activates
1) PDGF receptors have ___ tyrosine autophosphorylation sites. ___are in the split tyrosine kinase insert region!
_____ are on the C-terminal tail
2) What are the polypeptide positions/names of these tyrosine autophosphorylation sites?
PDGF(growth factor) receptors have 5 tyrosine autophosphorylation sites [3 in split tyrosine kinase insert region and 2 sites on C-terminal tail].
2)Insert region= 740, 751, 771
C-terminal tail = 1009 and 1021
What happens when mutations of tyrosine sites 1009 and 1021 occur?
Prevents binding and activation of a phospholipase-g (which has SH2 and SH3 domains SPECIFIC for these tyrosine sites)-->those sites no longer activate inositol signaling pathway.
2)How is this protein activated and how does it work when activated?
free standing cytoplasmic Tyrosine Kinase domain that temporarily has no mitogenic receptor commitment
2)Once ligand binds to mitogenic receptor, Src attaches to the receptor in Active Conformation and acts as the receptors Tyrosine Kinase domain
Different ____domains recognize different phosphotyrosine flanking ____ _____ ____.
2) This means what?
Different SH2 domains will recognize DIFFERENT phosphotyrosine flanking Amino Acid Sequences!
2) So...each domain has distinct sites for recognizing a specific AA side chain!
Describe the structure and binding ability of the SH2 domain 
Compact "plug-in" module inserted almost anywhere in a phosphorylated protein Tyrosine site WITHOUT disturbing folding or function :-)
[Has binding site for phosphotyrosine AND a binding site for the AA side chain SPECIFIC to that phosphotyrosine]
Where would the inactive Ras-GDP protein be located in the cell?
2)What activates/converts this protein?
Ras-GDP (and later Active Ras-GTP) is attached to the inner Plasma membrane by its embedded lipid tails
2) Ras-GDP is converted/ACTIVATED by Ras-GEF after Grb SH3 domains have bound
Ras-GEF full name is ?
Ras guanine nucleotide exchange factor (LIKE THE OTHER GEFs!)
___-____ Ras is present in about ___% of human cancers. These Ras genes are the most prominent of human _____.
2) Explain this particular mutation in Ras genes
3) How does GAP play a role in mutated Ras-GEF?
oncogenic-mutated Ras is in 30% of human cancers. These mutated Ras genes are MOST PROMINENET OF HUMAN ONCOGENES!
2)mutation in catalytic site AA[12, 13 or 61] of Ras-GEF inhibit its own GTPase activity which PREVENTS it from hydrolyzing GTP
= NO [Ras-GDPbut if Ras-GEF is MUTATED...GAP will no longer help :-((
A: Describe the LONG process of
MAP-kinase Ser/Thr phosphorylation pathway 
B: INCLUDE times gene expression is IMMEDIATE vs. delayed?
PATHWAY ACTIVATED BY [ACtive Ras-GTP] which will start by activating MAPKKK/RAF
-------(which then activates)--->MAPK/ERK
2)MAPK/ERK travels into nucleus and phosphorylates Fos which binds to AP1 element with Jun and creates Myc! [IMMEDIATE/early gene expression]
3)Myc goes on to stimulate G1 cyclin production[delayed gene xpression]---->G1 cyclin binds to G1-Cdk which [P] Rb to allow E2F to stimulate S-cyclin gene tx!
When E2F is freed by _______ it goes on to activate the tx of what exactly? 
When E2F is freed by phosphorylation of its binding father Rb(done by [G1-Cdk-cyclin] ) 1) E2F will go to activate
G1/S-cyclin(cyclin E)--->more Rb phosphorylation AND
2) MORE of E2F genes =
Oncogenic mutation is ____[recessive/Dominant] inheritance which means....
ONCOGENE mutation is Dominant! which means it only takes 1 bad allele of an oncogene--> CANCER/proliferation! THIS IS EVEN IF YOU HAVE BOTH TUMOR SUPPRESSOR GENES(recessive) WORKING smh
1) Tumor suppressor genes have ____[recessive/Dominant] inheritance.
2) What happens when you have 1 bad allele for Tumor suppressor genes?
1) Tumor suppressor genes have recessive inheritance
2)because recessive...only 1 bad allele will still allow other Normal allele to give a "haplosufficient" result = No tumors
*opposite of tumor suppressor gene and is essentially an oncogene in its INACTIVE state!
(possible chance it can become ACTIVE oncogene at any time :-/)
What are the 4 stages of Programmed cell death (AKA _____)
Apoptosis: 4 stages!
1st: Decision to kill a cell or give it another fate (based on Death Decision Box signals)
2nd: ACTUAL CELL DEATH [5 characteristics]
3rd: Phagocytic Engulfment of dead cell remains
4th: Degrade engulfed cell corpse
1) Apoptosis ?
2) List the 5 known characteristics of Apoptotic cell death
INTERNALLY encoded cell suicide program that does NOT involve Cell Lysing! and cell contents remain confined
1. Autodigestion of cell contents WITHOUT swelling and lysing
2. NO INFLAMMATORY RESPONSE
3. Loss of mitochondrial function
4. Nuclear DNA degraded into oligonucleosome fragments
5. cytoskeleton disruptions, cell shrinkage,membrane blebbing
How is T-cells related to Caspace proteins? 
1) T-cells secrete GRanzyme-B into the Caspace protein area and activates Caspace!-->PROMOTES APOPTOSIS
2)ALSO bind to Fas ligand (TNF Family) in "Death Decision Box" -->PROMOTES APOPTOSIS
What are the 2 jobs of Caspase protease proteins?
1. Hydrolyze peptide bonds of substrates intimately involved in signal cascade rxns
2. ALSO cleaves sister inactive Pro-Caspase--->ACTIVE CASPASE
How are Viruses related to Apoptosis?
2)What do normal BcL do?
Viruses make vBcL homologs to block Apoptotic pathway
--->they can use these jacked up cells to make more viral proteins smh
2) Normal BcL secreted from mitochondria ALSO BLOCKS Apoptotic pathway
Cell LYSE/Death --> Inflammatory response and rapid swelling!
What 4 signals are sent into the "Death/Central Decision Box" to carry out Apoptosis? [4 points]
DNA damage/Grwth factor withdrawal/TNF*Fas death receptors and p53 damage all activate Death/Central Decision box
----> Activation of Caspase Proteases---->Endonuclease Activation, Cell surface alteration, cytoskeleton changes
Viral Protein that BLOCKS Caspace protease activity preventing it from carrying out Apoptosis!
Name the Dzs that usually INHIBIT Apoptosis 
2. Autoimmune disorders
Name Dzs that INC Apoptosis 
B: Neurodegenerative disorders
C: Ischemic injury
stain that binds to cleaved DNA fragments (cleaved by endonucleases) = INDICATES IF APOPTOSIS IS OCCURRING!
Physiologic Blockers of Apoptosis 
1. Growth factors
2. Extracellular Matrix
Viral gene Blockers of Apoptosis 
1. Baculovirus p35
2. Cowpox virus crmA
Pharmacological Blockers of Apoptosis 
1. Cysteine protease inhibitors
2. Tumor promoters [phorbol ester]
Physiologic PROMOTERS of Apoptosis 
1. TNF family
2. Transforming growth factor
4. Grwth factor withdrawal
5. Matrix attachment loss
Damage-related PROMOTERS of Apoptosis 
1. Viral/Bacterial infection or toxins
2. Oncogenes = myc
3. Tumor suppressors = p53
4. Cytolytic T cells
5. Free radical Oxidants
6. Nutrient deprivation
7. Mitotic castrophe