细胞增殖及其调控 Cell proliferation and its regulation.ppt

Mitogens stimulate G1-Cdk and G1/S-Cdk activities A simplified model of one way that mitogens stimulate cell division DNA damage checkpoint: Cell-cycle progression is blocked by DNA damage and p53 How DNA damage arrests the cell cycle in G1. Two such checkpoints: 1.One in late G1: provents entry into S phase; 2.One in late G2: provents entry into mitosis; P53: gene regulatory protein.DNA damage activates p53 by an indirect mechanism. Mdm2 acts as a ubiquitin ligase that targets p53 for destruction by proteasomes. Phosphrylated p53 reduce its binding to Mdm2. P21(CKI protein) binds to G1/S-Cdk and S-Cdk and inhibits their activities, thereby helping to block entry into S phase. The summary of cell-cycle control system Summary An ordered sequence of cyclin-Cdk activities triggers most of the events of the cell cycle. During G1 phase, Cdk activity is reduced to a minimum by Cdk inhibitors(CKIs), cyclin proteolysis, and decreased cyclin gene transcription. When environmental conditions are favorable, G1- and G1/S-Cdks increase in concentration, overcoming these inhibitory barriers in late G1 and triggering the activation of S-Cdk. The S-Cdk phosphorylates proteins at DNA replication origins, initiating DNA synthesis through a mechanism that ensures that the DNA is duplicated only once per cell cycle. Once S-phase is completed, the activation of M-Cdk leads to the events of early mitosis, whereby the cell assembles a mitotic spindle and prepares for segregation of the duplicated chromosomes---which consist of sister chromatids glued together. Ananphase is triggered by the destruction of the proteins that hold the sisters together. The M-Cdk is then inactivated by cyclin proteolysis, which leads to cytokinesis and the end of M phase. Progression through the cell cycle is regulated precisely by various inhibitory mechanisms that arrest the cell cycle at specific checkpoints when events are not completed successfully, when DNA damage occurs, or when extracellular condi