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3 checkpoints that detect state of chromosomes (not DNA damage)
1. Intra-S-phase checkpoint
2. Spindle assembly checkpoint
3. Spindle position checkpoint
- -point in cell cycle when cell "commits" to entering S phase and completing cell cycle
- -happens late in G1 phase
- -Before START point, E2F inactive. After START point, E2F is active!
- -E2F is a transcription factor. It binds to DNA and causes transcription activation.
- -transcribes genes encoding DNA replication and S phase cyclin/Cdks.
- -is a "delayed response gene"
- -activated by cFos
Mechanism for activation of E2F
- 1. Mitogen binds to mitogen receptor
- 2. mitogen receptor is activated and activates Ras
- 3. Ras triggers MAP kinase cascade
- 4. MAP kinase cascade leads to transcription/translation of immediate early genes (one gene being Myc)
- 5.Myc (a regulatory protein) binds to G1-Cdk and activates it indirectly
- 6. activated G1-Cdk phosphorylates Rb protein
- -Rb protein is an inhibitory protein. Before phosphorylation, Rb attaches to E2F and keeps it inactivated. Once phosphorylated, it unbinds from E2F.
- 7. Rb protein then releases E2F...E2F is now free and active!
Possible changes in E2F activation in Cancer cells
- 1. Rb is inactivated by another mean (mutant Rb)
- -retinoblastoma cancer has a mutant Rb...E2F is always active!
- -Rb mutation is a loss of function mutation
- 2. Ras is always active (mutant Ras)
- -phosphorylation of Rb would no longer be dependent on mitogen
- -gain of function mutation
- -Ras mutation is 2nd most common cause of cancer
- 3. Gain of function of Myc
- -cause of many blood cancers
Gain of function vs Loss of function mutations
- -Both lead to deregulated cell division
- -Gain of Function: are promoters. called oncogenes
- -Loss of Function: are tumor suppressor genes