Hypoxic Suppression of the Cell Cycle GeneCDC25Ain Tumor Cells

Abstract

Hypoxia, a key microenvironmental factor for tumor development, not only stimulates angiogenesis and glycolysis for tumor expansion, but also induces cell cycle arrest and genetic instability for tumor progression. Several independent studies have shown hypoxic blockade of cell cycle progression at the G 1 /S transition, arising from the inactivation of S-phase-promoting cyclin E-CDK2 kinase complex. Despite these findings, the biochemical pathways leading to the cell cycle arrest remain poorly defined. We recently showed that hypoxic activates the expression of CDNK1A encoding the CDK2 inhibitor p21 Cip1 , through a novel HIF-1a-Myc pathway that involves Myc displacement from the CDNK1A promoter by the hypoxia-inducible transcription factor HIF-1a. In pursuit of further understanding of the hypoxic effects on cell cycle in tumor cells, here we report that hypoxia inhibits the expression of CDC25A, another cell cycle gene encoding a tyrosine phosphatase that maintains CDK2 activity. In accordance with the HIF-1a-Myc pathway, hypoxia requires HIF-1a for CDC25A repression, resulting in a selective displacement of an activating Myc from the CDC25A promoter without affecting a canonical Myc binding in the intron. Intriguingly, HIF-1a alone fails to recapitulate the hypoxic effect, indicating that HIF-1a is necessary but insufficient for the hypoxic repression. Taken together, our studies indicate that hypoxia inhibits cell cycle progression by controlling the expression of various cell cycle genes.

A mathematical model of HiF-1-mediated response to hypoxia on the G1/S transition

“…Many reports show that HiF-1 inhibits the cyclin D [50,16] and the cyclin E [22,19,1] leading to the cell cycle arrest. However, an other report [3] shows that HiF-1 can also stimulate the induction of cyclins D, leading to cell proliferation.…”

“…A review of the huge molecular biology literature dealing with the effects of HiF-1α on the cell cycle enables us to retain several types of actions. First, it is clear that HiF-1α indirectly downregulates cyclin E activity, and this inhibition is the reason why HiF-1α causes slowing down or arrest of cell cycle [22,19,1].…”

“…The origins of this action on cyclin E activity remain poorly defined [22], even if some potential pathways are known. Notably, the upregulation of cyclins inhibitors, such as p21 and p27, are reported [17,22,20].…”

“…Notably, the upregulation of cyclins inhibitors, such as p21 and p27, are reported [17,22,20]. However, some authors showed that the action of HiF-1α on p27 is not so clear since the expression of p27 under hypoxia may be independent of HiF-1α [6,9].…”

Carrot and stick: HIF-α engages c-Myc in hypoxic adaptation

“…Interestingly, although both NBS1 and CDC25A genes harbor an E-box element in their introns, no significant changes in c-Myc binding to the E-box have been detected when gene expression is suppressed. 39,40 Therefore, it appears that HIF-1a selectively targets c-Myc bound indirectly to DNA via another transcription factor for displacement (Figure 2b). Such a selective mechanism may explain the relatively weak suppression (approximately two-to threefold) of these genes by hypoxia, because of the remnant c-Myc-activating activity bound to the E-box.…”