A simplified scheme indicating the role of serine/threonine phosphorylation events in regulating DNA-damage-induced cell cycle checkpoint control: DNA damage results in phosphorylation-mediated stabilization of p53 by a variety of kinases (ATM, ATR, DNA-PK, Jnk, and CKI). This blocks the interaction of p53 with Mdm2 that normally results in efficient ubiquitin-targeted degradation of p53 by the proteasome. Activated p53 induces the transcription of genes such as p21cip1/waf1, a cyclin dependent kinase inhibitor (CKI) that blocks the action of CyclinE/Cdk2 and thereby prevents the phosphorylation of targets such as Rb, an event that is required for G1 to S transition. DNA damage stabilization of p53 thereby blocks cell cycle progression at the G1 to S checkpoint. Cyclin E1 is itself degraded at the G1 to S boundary following phosphorylation on Thr-380. Phosphorylation at this site is sufficient to target Cyclin E1 to the SCF E3 ubiquitin ligase complex composed of cdc53/CUL-1, Skp1, Rbx-1, cdc34 (E2), and a putative F-box protein. DNA damage also results in the activation of Chk1 kinase that phosphorylates the Cdc25C phosphatase on Ser-216. 14-3-3 protein binds to phosphorylated Cdc25C and sequesters this complex in the cytoplasm. Active Cdc25C is required to activate CyclinB/Cdk2 to allow G2 to M transition. Thus, DNA damage also blocks cell cycle progression at the G2 to M checkpoint.
Copyright © 2001-2005 Daniele Focosi.
All rights reserved
| Terms of use | Legal
notices
|
|
|
|
|
