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85 Cards in this Set

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  • Back
2 Ways that the cell cycle is regulated:
1. Externally via growth factors binding receptors
2. Internally via 2nd msgrs that stimulate gene expression
2 types of external cell cycle regulators:
-growth factors
3 stages of intracellular cell cycle regulation:
1. Early response genes
2. Progression factor genes
2. Delayed response genes
What are the early response genes?
c-fos, c-myc, jun
What is the progression factor gene?
What are the delayed response genes?
Cyclins and CDKs
What are CDKs and Cyclins?
Cyclin-dependent protein kinases - activated in the nucleus to phosphorylate unknown nuclear proteins.
What does phosphorylating nuclear proteins do?
What is a cdk, structurally?
A dimer of 2 things - one a member of the Cdk family, the other from the Cyclin family.
What is the subunit from the CDK family?
The catalytic subunit that phosphorylates target proteins.
How many types of Cdks are there?
What happens to its content during the cell cycle?
2 - Cdk content remains constant.
What is the Cyclin subunit?
The regulatory subunit that controls kinase activity
How many cyclins are there?
6 - A through F
What happens to the content of a cyclin during the cell cycle?
It changes - cycles
What are the 3 major checkpoints in the cell cycle?
1. G1/S
2. G2/M
3. Metaphase/Cytokinesis
What are the CDKs?
1,2,4,6 - there must be four
What is the term for the G1/S checkpoint?
What dimers regulate the G1/s restriciton point?
CDK-2 + cyclin E
CDK-2 + cyclin A
What is determined by the G1/S restriction point?
If the cell gets past it, it's committed to go to the next checkpoint.
What is the G2/M checkpoint regulator?
CDK-1 + cyclin B
What is another name for CDK1 + Cyclin B?
MPF - M-phase promoting factor
What is required for MPF to be active?
What happens when active MPF reaches a critical concentration?
Mitosis is ignited and MPF phosphorylates and activates a protein cascade.
What is one of the proteins phosphorylated by MPF?
Histone H1
So the result of MBF phosphorylation and activation of a protein cascade is:
What regulates the Metaphase-Cytokinesis checkpoint?
Ubiquitin-mediated degradation of cyclin-B
What happens when cyclin-B is degraded?
Phosphorylation is reversed, cytokinesis and G1 ensue
So what is the major difference between the metaphase-cytokinesis checkpoint and the 2 before it?
It is NOT regulated by a cyclin/cdk dimer!
4 points at which the cell cycle is activated:
What activates G1?
CDK4/CDK6 + cyclin D
What are 3 actions of CDK4/6 + CYCLIN D?
1. phosphorylates transcription factors and polymerases that activate S phase
2. Phosphorylates Retinoblastoma protein
3. Ubquitinates cell cycle inhibitory factors for destruction
What does Retinoblastoma do?
Liberates E2F-1 which activates cell cycle genes.
What activates R (restriction point)?
CDk2 + Cyclin E
What activates S?
CDK2 + Cyclin A
2 Actions of CDK2+cyclin A:
1. Phosphorylate replicons
2. Inhibits formation of new replicons
-Daughters get the same DNA complement
What activates M checkpoint?
CDK1 + Cyclin B (MPF)
what does MPF do?
Causes chromosome condensation and mitotic spindle assembly
What is APC?
Anaphase promoting complex
What does APC do?
Ubiquitinates kinetochore proteins and cyclin B to allow the cell cycle to proceed into anaphase.
4 Things responsible for cell-cycle Repression:
1. Retinoblastoma
2. p21
3. p53
4. p38 MAP kinase
What does Retinoblastoma do?
Binds E2F1 and prevents it from transactivating cell cycle genes.
What does P21 do?
Directly inhibits CDK2 and CDK4
What does p53 do?
Induces p21 and apoptosis
What is the main thing to remember about Cancer?
It is a genetic disease
4 Major characteristics of cancer:
1. Ch' rearrangmt, loss, & gain
2. Mutant cell clone expansion
3. Dcrsd cell differentiation, increased proliferation
4. Pathogenic invasiveness
What are causes of cancer?
-Accumulated environmental insults
-Aging of cells - evolution toward malignancy
What does "self sufficiency in growth signals" refer to?
The conversion of protooncogenes to oncogenes.
Why do oncogenes cause cancer?
Because the mutated genes control growth factors, GF receptors, 2nd msgrs, trscrpn factors, and checkpoint regulatory proteins.
4 examples of oncogenes:
-cyclin D1
What is src?
A tyrosine kinase - the 1st oncogene discovered
What is ras?
a GTP binding protein that is mutated in 30% of cancers.
What is cyclin D1?
another oncogene
What is EGFR?
epidermal growth factor receptor
What type of mutations are the ones that cause protooncogenes to become oncogenes?
Gain of function
Why do oncogenes cause cancer?
Because they are growth factors that are overactive - constitutive.
How does insensitivity to anti-growth signals develop?
Cells that normally suppress tumors no longer have potency.
What are 4 normal tumor suppressor genes that cancer becomes insensitive to?
-Rb (retinoblastoma)
What is the normal job of retinoblastoma?
Inhibits transcription factors (E2F1) that promote cell division.
Why does insensitivity to p53 cause cancer?
Because normally p53 inhibits the cell cycle by increasing p21 and by activating apoptosis (pcd)
How does Tip60 function?
akin to p53
What is the result of mutations in antigrowth signals?
Immortal cell proliferation
How do mutations causing immortal cell proliferation differ from protooncogenes?
These are loss of function; protooncogenes are gain of function mutations.
What is PCD?
Apoptosis - programmed cell death - a normal and necessary biological process.
What triggers PCD?
Ca endonuclease
3 things that happen when Ca-endonuclease triggers PCD:
1. Chromatin condensation and fragmentation
2. Blebs on cell surface
3. Defoliation of the cell
How does PCD relate to cancer?
PCD retards tumor growth
What is bcl-2?
B-cell lymphoma gene that is mutated and OVERDOES its normal job of inhibiting PCD
Why is it bad when PCD is overinhibited?
Not enough cell death occurs and tumors grow
Why do cells normally have a finite lifespan?
B/c at each generation they lose some telomere DNA
When happens when cells lose a pre-determined amount of their telomere dna?
They enter replicative senescence.
What maintains telomere length?
What cells have telomerase?
Embryonic stem cells and germline cells ONLY!
What is the result of a mutated telomerase?
Constitutive activity - immortality of cells.
What type of mutation is that of bcl-2?
Gain of function - it becomes overactive in inhibiting PCD.
What type of mutation is that of telomerase?
Gain of function - it becomes overactive in maintaining telomreres.
What is another type of mutation that can result in limitless replicative potential (immortality)?
Mutation of DNA repair genes
What results when DNA repair genes are mutated? give an example:
Clones of cancer cells - e.g. colorectal cancer
What type of mutation is it when DNA repair genes are damaged?
Loss of function
What is the disadvantage of cancer in terms of management?
Treatment is nonspecific
What are 2 promising types of therapy that might be more specific treatments of cancer?
-siRNA based chemo
What is a TIMP?
Tissue inhibitor of metalloproteinases
Why target metalloproteinases?
Because they have been identified in facilitating cancer by letting cells escape the primary tumor and metastesize.
How do cancer cells metastesize?
By eating their way through organs and taking up residence in other places.
What molecules allow metastesis?
What is a final hallmark of cancer?
Sustained angiogenesis