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细胞周期调控机理

The G1/S cell cycle checkpoint controls the passage of eukaryotic cells from the first éŸap? phase (G1) into the DNA synthesis phase (S). Two cell cycle kinases, CDK4/6-cyclin D and CDK2-cyclin E, and the transcription complex that includes Rb and E2F are pivotal in controlling this checkpoint. During G1-phase, the Rb-HDAC repressor complex binds to the E2F-DP1 transcription factors, inhibiting the downstream transcription. Phosphorylation of Rb by CDK4/6 and CDK2 dissociates the Rb-repressor complex, permitting transcription of S-phase genes encoding for proteins that amplify the G1- to S-phase switch and that are required for DNA replication. Many different stimuli exert checkpoint control including TGFbeta, DNA damage, contact inhibition, replicative senescence and growth factor withdrawal. The first four act by inducing members of the INK4 or Kip/Cip families of cell cycle kinase inhibitors. TGFbeta additionally inhibits the transcription of Cdc25A, a phosphatase that activates the cell cycle kinases. Growth factor withdrawal activates GSK-3beta, which phosphorylates cyclin D, leading to its rapid ubiquitination and proteosomal degradation. Ubiquitination, nuclear export and degradation are mechanisms commonly used to rapidly reduce the concentration of cell cycle control proteins.

 

The G2/M DNA damage checkpoint prevents the cell from entering mitosis (M-phase) if the genome is damaged. The cdc2-cyclin B kinase is pivotal in regulating this transition. During G2-phase, cdc2 is maintained in an inactive state by the kinases Wee1 and Myt1. As cells approach M phase, the phosphatase cdc25 is activated, perhaps by the polo-kinase Plk1. Cdc25 then activates cdc2, establishing a feedback amplification loop that efficiently drives the cell into mitosis. DNA damage activates the DNA-PK/ATM/ATR kinases, initiating two parallel cascades that inactivate cdc2-cyclin B. The first cascade rapidly inhibits progression into mitosis: the Chk kinases phosphorylate and inactivate cdc25, which can no longer activate cdc2. The second cascade is slower. Phosphorylation of p53 dissociates it from MDM2, activating its DNA binding activity. Acetylation by p300/PCAF further activates its transcriptional activity. The genes that are turned on by p53 constitute effectors of this second cascade. They include 14-3-3, which binds to the phosphorylated cdc2-cyclin B kinase and exports it from the nucleus; GADD45, which apparently binds to and dissociates the Cdc2-cyclin B kinase; and p21Cip1, an inhibitor of a subset of the cyclin-dependent kinases including Cdc2 (CDK1).

 

The cell cycle is regulated by the interplay of many molecules. Key among these are the cyclins which are expressed and then degraded in a concerted fashion to drive the stages of the cell cycle. Cyclins combine with cyclin dependent kinases (cdks) to form activated kinases that phosphorylate targets leading to cell cycle regulation. A breakdown in the regulation of this cycle can lead to out of control growth and contribute to tumor formation. Defects in many of the molecules that regulate the cell cycle have been implicated in cancer. Key among these are p53, the cdk inhibitors (p15, p16, p18, p19, p21, p27), and Rb, all of which act to keep the cell cycle from progressing until all repairs to damaged DNA have been completed.

 

 

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