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p57^Kip2, a Glucocorticoid-Induced Inhibitor of Cell Cycle Progression in HeLa Cells

Department of Medical Nutrition Karolinska Institute Huddinge University Hospital, Novum F60 SE-141 86 Huddinge, Sweden

Glucocorticoids exert antiproliferative effects on a number of cell types, including the HeLa cervical carcinoma cell line. However, the mechanism responsible for the antiproliferative effect is poorly understood. In this report we have investigated the role of the recently identified cyclin-dependent kinase inhibitor (CDI) p57^Kip2 in the antiproliferative effect conferred by glucocorticoids. When HeLa cells were treated with the synthetic glucocorticoid dexamethasone (DEX), the doubling time of exponentially growing cells increased 2-fold. Within 11 h of DEX treatment, this was accompanied by an accumulation of cells in the G₁ phase of the cell cycle with a corresponding decreased proportion of cells in the S phase and decreased CDK2 activity. DEX treatment of the HeLa cells dramatically induced the protein and mRNA expression of the CDI p57^Kip2. This induction was seen within 4 h of DEX treatment, preceding a major DEX-induced accumulation of cells in the G₁ phase. DEX-induced mRNA expression of p57^Kip2 did not require de novo protein synthesis, and the transcription of the p57^Kip2 gene was increased as determined by a run-on transcription assay. Furthermore, DEX induction of p57^Kip2 was not a consequence of the cell cycle arrest, since other growth inhibition signals did not result in strong p57^Kip2 induction. Overexpression of p57^Kip2 using HeLa cells stably transfected with a tetracycline-inducible vector showed that p57^Kip2 is sufficient to reconstitute an antiproliferative effect similar to that seen in DEX-treated cells. Selective p57^Kip2 expression by the tetracycline analog doxycycline to levels comparable to those observed on DEX induction resulted in a 1.7-fold increase in the doubling time and a shift of HeLa cells to the G₁ phase as well as a decrease in CDK2 activity. Taken together, these results suggest that glucocorticoid treatment directly induces transcription of the p57^Kip2 gene and that the p57^Kip2 protein is involved in the glucocorticoid-induced antiproliferative effect.

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