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33 Cards in this Set
- Front
- Back
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stages of the cell cycle |
G1, S, G2, M
duration of different stages of cell cycle vary in different organisms and at different stages of development |
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G1 phase |
at the end of G1 phase, G1/S and S-phase cyclin-Cdk is activated |
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S phase |
only S-cdk-cyclin is active --> S phase replication of DNA |
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G2 phase |
at end of G2 and beginning of M, M phase cyclin-Cdk is activated |
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M phase |
mitosis: prophase, metaphase, anaphase, telophase, cytokinesis
mid M phase: cylins and sister chromatid cohesion are degraded |
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rationale for chromosome condensation and sister chromatid cohesion |
separation of chromatids without tangling |
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mitotic spindle |
-aster microtubules radiate out from centrosome in all directions; associate with membrane and pull centrosome away from metaphase plate -kinetochore microtubles bind the kinetochore on the sister chromatids; are shortened to pull sister chromatids apart -interpolar microtubles overlap at the metaphase plate, and provide motor protein pushing/sliding force to separate centrosomes -self organizes: growing and shrinking MTs radiating from centrosome encounter and bind kinetochores; preformed MTs are captured by centrosomal MTs and pulled in |
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control of cdks |
-accumulation of cyclins -phosphorylation -Cdk inhibitors (CKIs) -proteolytic degredation |
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SCF and APC ubiquitin ligase complexes |
-SCF: active at G1/S transition; multiple F-box proteins allow it to target multiple substrates (e.g. G1/S cyclins and cdk inhibitors); most F-box proteins bind to phosphorylated targets, so SCF couples phosphorylation with irreversible degredation -APC: active at metaphase to degrade M cyclins and proteins that hold sister chromatids together; is activated by M-cdk (turns itself off/provides negative feedback for M-cdk)
these complexes link the phosphorylation of or by cyclin-CDK to their degredation (progress begets further progress, no going back) |
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biochemical oscillators |
-achieved with a delayed negative feedback loop (e.g. the M-cdk's activation of APC, which then ubiquitinizes M-cdk) |
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overall logic of the cell cycle control system |
at each stage the machinery acts to reinforce the current stage, inhibit the preceding stage, and prepare for the next stage |
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control of cdks by levels of cyclin |
cyclin levels are regulated by transcription and degredation; which cyclin is at highest concentration helps determine which cdk-cyclin is active b/c cyclin is essential for active cdk |
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control of cdks by phosphorylation |
cyclin-cdk must have positive phosphorylation (Thr160) to be active, but also must not have negative phosphorylation (Thr14/Thr15)
negative phosphorylation by Myt1 or Wee1 dephosphorylation by Cdc25, which serves as a trigger |
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control of cdks by cdk inhibitors |
CKIs bind and inhibit active site of cdk two different classes of CKIs inhibit different cdks |
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control of cdks by proteolytic degredation |
-cdk-cylins become ubiquitinized so are degrades by the proteasome -two ubiquitin ligase complexes (SCF and APC) regulate the cell cycle by targeting proteins for destuction
-protein degradation is great because it is an irreversible control, thus it ensures that once a particular stage of the cell cycle is attained, it cannot easily go back |
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bistable switch |
-simple regulation by interaction of two components leads to a graded response (as ligand increases, so too does activated protein) -cell cycle needs a switch -established by having multiple positive feedback loops (i.e. activated cyclin-cdk provides additional activation of its activator and inhibition of its inhibitor) |
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role of START |
-key checkpoint (G1 checkpoint) -past START there's no going back, you have to replicate the genome and divide -ask are mitogens present? is the cell big enough? is DNA intact? -might be part of the genetic program to not go through START after differentiation |
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mechanism of START |
-mitogen binds mitogen receptor -receptor activates G1-cdk -G1-cdk phosphorylates Rb (inhibiting it) -inactive Rb releases E2F (activating) -active E2F promotes transcription of G1/S genes |
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mechanisms of activation of G1-cdks |
-ras pathway -PI-3 kinase/Atk pathway
-both stimulated by mitogens |
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RAS pathway |
-leads to transcription of G1 and G1/S genes -activation of Ras by mitogens activates a kinase cascade leading to activation of MAPK (mitogen activated protein kinase) -MAPK phosphorylates nuclear factors that promote transcription of immediate early genes |
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PI-3 kinase/Atk pathway |
-provides mitogenic signal -promotes cell growth and cell survival |
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checkpoints |
-provides moment for the cell cycle to be arrested if conditions are not appropriate -arrest can be temporary (until problem is fixed) or permanent (G1 arrest) -in extreme cases, damage induces apoptosis -START: are mitogens present; is cell big enough; is DNA intact? -G2/M: is DNA replication complete? is DNA intact? -metaphase-to-anaphase: is spindle assembly complete? are all chromosomes attached to spindle? |
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role of p53 |
-guardian of the genome -transcription factor that promotes transcription of cell cycle inhibitors and regulators of apoptosis -in undamaged cells p53 associates with a ubiquitin ligase Mdm2, so is short-lived -in stressed cells, p53 is phosphorylated, tetramerized, and actively promotes transcription of all those bad things |
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difference between proliferation and cell growth |
-proliferation: regulated by mitogens -cell growth: regulated by growth factors (which mostly regulate rate of protein synthesis and degredation (e.g. TOR pathway) |
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cancer is the result of... |
accumulated genetic mutations and selection for growth and survival |
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oncogene |
-genes that promote cell growth, division, and survival -are dominant because their abnormally high level causes phenotype -e.g. Ras |
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tumor suppressor |
-genes that regulate and inhibit cell cycle -are recessive because they need to lose function from both alleles in order to have a seen effect -e.g. Rb |
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two ways to lose normal growth control |
-overactivity of pathways that stimulate proliferation and survival (accelerator is stuck). caused by mutation or amplification of oncogenes -inactivation of pathways that normally act to inhibit cell proliferation or induce cell death (breaks don't work). caused by mutation/deletion of tumor suppressor genes |
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how tumors overcome cellular defense mechanisms |
-force the cell into cell cycle -subvert normal checkpoint responses -avoid senescence |
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mitogens |
-can be peptide or lipid -encourages cell division (mitosis) |
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DNA damage response |
-blocks cell cycle when DNA is damaged -kinases recruited to sites of DNA damage and activated -leads to either production of DNA repair enzymes, reversible cell-cycle arrest, or permanent cell-cycle arrest or cell death |
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hyper-proliferative response |
-cell cycle will not proliferate when something is "not right" (discordant or excess signaling) -leads to ARF (Mdm2 inhibitor) allowing p53 to do its thing |
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TOR pathway |
-activated by G protein Rheb -leads to increased ribosome production and protein synthesis |
