Role of the Steroid Receptor Coactivator SRC-3 in Cell Growth

Abstract

Steroid receptor coactivator 3 (SRC-3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 (NCoA-1) and SRC-2 (TIF2/GRIP1/NCoA2). Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines. Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size. Similarly, in SRC-3 null mutant mice, AKT signaling is down-regulated in normally SRC-3-expressing tissues. Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth.

ACKNOWLEDGMENTS

This work is supported by NIH grants to S.Y.T. (DK57743, project 3) and M.-J.T. (DK62821 and CA58204). G.Z. is supported by a Fellowship of DOD for Prostate Cancer Research (DAMD 17-99-1-9509).

We thank Francesco J. DeMayo, Debra E. Bramblett, Sue-Hwa Lin, David M. Lonard, Xiaotao Li, and Ray-chang Wu for discussions and helpful comments on the manuscript. We are also grateful to Liliang Wang and Baolin Liu for providing technical assistance.