Regulation of the cdk inhibitor p21 gene during cell cycle progression is under the control of the transcription factor E2F

Abstract

The control of cell cycle progression is orchestrated by an extraordinary diverse and dynamic in function group of proteins. Critical in the progression are the actions of the E2F family of transcription factors which regulate the expression of genes necessary for the G 1 /S transition and the WAF/CIP/KIP family of cdk inhibitors which can inhibit cell cycle progression. In this report, we have identi®ed E2F binding sites in both the human and mouse p21 promoters that bind E2F protein complexes from nuclear extracts in a cell cycle-dependent manner. In ectopic expression experiments we determined that E2F1, but not E2F4, can strongly transactivate the human p21 gene through these E2F binding sites which are located in the 7215/+1 region of the p21 gene. The transactivation of the p21 gene through regulatory elements within the 7215/+1 region of the promoter was correlated with increased levels of endogenous E2F1 and p21 proteins at the G 1 /S boundary. The signi®cance of transactivation of the p21 gene by E2F is that p21 function is important in cell cycle progression as well as for cell cycle arrest. Indeed, E2F-induced levels of p21 protein during the G 1 / S transition is consistent with the recent ®ndings demonstrating that p21 acts as an assembly factor for kinase active cyclin/cdk/p21 complexes.

p53 gene transfer does not enhance E2F-1-mediated apoptosis in human colon cancer cells

“…It is well documented that factors other than p53 can induce p21 gene expression (Li et al, 1995;Halevy et al, 1995;Qiu et al, 1996;Greenhalgh et al, 1996;Billion et al, 1996;Lee et al, 1998). Our data suggest that E2F-1 may have a similar ability to induce p21 under certain circumstances and is in agreement with a recent study where E2F-1 was found to transactivate p21 (Hiyama et al, 1998). Although one study reported that p21 growth arrest fails to protect gliomal cells from E2F-1-mediated apoptosis (GomezManzano et al, 1999), a growing body of evidence now points to an opposing relationship between E2F-1 and p21 in both cell cycle control and induction of apoptosis (Chen et al, 1995;Shiyanov et al, 1996;Dimri et al, 1996;Hiyama et al, 1998;Delavaine and La Thangue, 1999).…”

“…Recently, E2F-1 has also been shown to upregulate p21 and subsequently, E2F-1 activity is inhibited, thus forming a negative feedback loop (Hiyama et al, 1998). To further investigate the mechanisms of E2F-1 and p53 interactions, we probed for p21.…”

Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

“…The p21 WAF1/CIP1 accumulation may also be induced by the activation of alternative pathways. For instance, it was demonstrated that the p21 WAF1/CIP1 gene is regulated by the transcription factor E2F, which is normally activated in HPV-infected cells (Hiyama et al, 1998). Another possibility would be the transactivation pathway through p53 (Macleod et al, 1995).…”

C-terminal deletion mutant p21WAF1/CIP1 enhances E2F-1–mediated apoptosis in colon adenocarcinoma cells

“…25,26 Interestingly, a recent study demonstrated that E2F -1 directly transactivates p21, and subsequently, E2F -1 transcriptional activity is inhibited. 27 Collectively, the evidence suggests a feedback loop mechanism between E2F -1 and p21 with apparently opposing activities that involve both direct and indirect interactions. 26,28,29 The mechanism( s ) of E2F -1 -mediated apoptosis are not completely elucidated.…”