Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
85 Cards in this Set
- Front
- 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:
|
-cytokines
-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?
|
PCNA
|
|
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?
|
REGULATES THE CELL CYCLE
|
|
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?
|
The RESTRICTION point
|
|
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?
|
Phosphorylation
|
|
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:
|
MITOSIS
|
|
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:
|
G1
R S M |
|
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:
result? |
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:
|
-src
-ras -cyclin D1 -EGFR |
|
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)
-BRCA -Tip60 -p53 |
|
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?
|
Telomerase
|
|
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?
|
-TIMPS
-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?
|
Proteinases
|
|
What is a final hallmark of cancer?
|
Sustained angiogenesis
|