DIETARY MODULATION OF CELL CYCLE REGULATORS

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The cyclin-dependent kinase inhibitors are a recently characterized class of proteins that regulate cell number homeostasis and progression of the cell cycle. One of these, p21WAF1/CIP1, can be transcriptionally activated by the tumor suppressor p53 (especially in response to DNA damage) and so links regulation of the cell cycle and tumorigenesis. Transcription of p21 can also be induced independently of p53. One effect of p21 is to cause an arrest of the cell cycle at the G1 phase; depending on the cell type, this G1 arrest can allow time for repair of damaged DNA or lead to apoptotic cell death. Cells that lack p53 function cannot induce p53- dependent expression of p21 and display increased genomic instability and decreased cell cycle transit time. Following up on the link between p53 and p21, we examined the expression of p21 in the p53- deficient mouse and showed that dietary and chemopreventive interventions that significantly delay the inevitable development of spontaneous tumors in this model also modulate p21 expression. Among these successful manipulations is dietary administration of dehydroepiandrosterone (DHEA), an adrenal steroid with global metabolic effects in addition to its chemopreventive activity. To study the effects of various agents on expression of cell cycle regulators more directly in an in vitro model system, we have developed embryonic fibroblast cell lines from fetuses with or without p53. In this system DHEA indeed slowed the cell cycle, even in p53- deficient cells, but had no direct effect on genomic stability. We are currently developing p21 constructs to investigate the possibility that some of the other actions of DHEA or related steroids may require the induction of p21. These constructs will also be used to address more general questions concerning the role of p21 in regulation of metabolism. In addition we are investigating the expression of other cell cycle regulators in response to dietary interventions.