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