Abstract
p53 represses the transcription of cdc2 and cyclin B1, causing loss of Cdc2 activity and G(2) arrest. Here we show that the region -22 to -2 of the cdc2 promoter called the R box is required for repression by p53 but not for basal promoter activity. The R box confers p53-dependent repression on heterologous promoters and binds to p130/E2F4 in response to overexpression of p53. R box-dependent repression requires p21/waf1, and overexpression of p21/waf1 also represses the cdc2 promoter. These observations suggest that p53 represses the cdc2 promoter by inducing p21/waf1, which inhibits cyclin-dependent kinase activity, enhancing the binding of p130 and E2F4, which together bind to and repress the cdc2 promoter.
Highlights
The p53 tumor suppressor protects mammals from neoplasia by eliminating cells containing damaged DNA through apoptosis or cell cycle arrest [1, 2]. p53-dependent arrest in response to DNA damage occurs in both G1 and G2 phases of the cell cycle [3,4,5,6]. p53 controls progression through S phase when nucleotide pools are out of balance, avoiding DNA damage, and inhibits entry into mitosis when DNA synthesis is blocked [7,8,9]
Cdc2 is normally regulated by phosphorylation, by its binding to Cyclin B, and by nuclear localization [29, 30]. p53 can inhibit the cyclin-dependent kinase (CDK)-activating kinase, which activates Cdc2 by phosphorylating threonine 161 [31, 32]. p21/waf1 associates with Cdc2/ Cyclin B1 in cells arrested by p53 in G2, suggesting an additional layer of inhibition [28]
E2F4/p130 Binds to the R Box of the cdc2 Promoter to Mediate Repression by p53—We investigated which downstream targets of p53 and p21/waf1 might mediate repression of the cdc2 promoter. p130 and E2F4 bind to the putative E2F site that overlaps the cycle-dependent element (CDE) of this promoter and have been implicated in the repression observed in G0 and G1 (Ref. 54 and Fig. 2B). p21/waf1 can inhibit the ability of Cyclin/CDK complexes [12] to phosphorylate the Rb family members pRb, p107 and p130 [60, 61]
Summary
The p53 tumor suppressor protects mammals from neoplasia by eliminating cells containing damaged DNA through apoptosis or cell cycle arrest [1, 2]. p53-dependent arrest in response to DNA damage occurs in both G1 and G2 phases of the cell cycle [3,4,5,6]. p53 controls progression through S phase when nucleotide pools are out of balance, avoiding DNA damage, and inhibits entry into mitosis when DNA synthesis is blocked [7,8,9]. We demonstrate that p53 represses the cdc2 promoter through a mechanism involving induction of p21/waf1 and binding of the Rb family protein p130 and the transcription factor E2F4 to the CDE and CHR elements within the R box of the cdc2 promoter.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
