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TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21^WAF1/Cip1 and p27^Kip1

Florence Gizard,^1,2, Romain Robillard,^2, Olivier Barbier,² Brigitte Quatannens,³ Anne Faucompré,² Françoise Révillion,⁴ Jean-Philippe Peyrat,⁴ Bart Staels,^1* and Dean W. Hum^1,5*

Centre de Recherche en Endocrinologie Moléculaire et Oncologique, Université Laval, Québec G1V 4G2, Canada,¹ U545 INSERM, Département d'Athérosclérose,² FRC3 CNRS, Institut de Biologie de Lille et Institut Pasteur de Lille,³ Laboratoire d'Oncologie Moléculaire Humaine, Centre Oscar Lambret, Lille,⁴ Genfit, Parc Eurasanté, Loos, France⁵

Received 17 August 2004/ Returned for modification 23 September 2004/ Accepted 20 February 2005

The transcriptional regulating protein of 132 kDa (TReP-132) has been identified in steroidogenic tissues, where it acts as a coactivator of steroidogenic factor 1 (SF-1). We show here that TReP-132 plays a role in the control of cell proliferation. In human HeLa cells, TReP-132 knockdown by using small interfering RNA resulted in increased G₁S cell cycle progression. The growth-inhibitory effects of TReP-132 was further shown to be mediated by induction of G₁ cyclin-dependent kinase inhibitors p21^WAF1 (p21) and p27^KIP1 (p27) expression levels. As a consequence, G₁ cyclin/cyclin-dependent kinase activities and pRB phosphorylation were markedly reduced, and cell cycle progression was blocked in the G₁ phase. The stimulatory effect of TReP-132 on p21 and p27 gene transcription involved interaction of TReP-132 with the transcription factor Sp1 at proximal Sp1-binding sites in their promoters. Moreover, in different breast tumor cell lines, endogenous TReP-132 expression was positively related with a lower proliferation rate. In addition, TReP-132 knockdown resulted in enhanced cell proliferation and lowered p21 and p27 mRNA levels in the steroid-responsive and nonresponsive T-47D and MDA-MB-231 cell lines, respectively. Finally, a statistic profiling of human breast tumor samples highlighted that expression of TReP-132 is correlated with p21 and p27 levels and is associated with lower tumor incidence and aggressiveness. Together, these results identify TReP-132 as a basal cell cycle regulatory protein acting, at least in part, by interacting with Sp1 to activate the p21 and p27 gene promoters.

F.G. and R.R. contributed equally to this study.

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