Role of the steroid receptor coactivator SRC-3 in cell growth.
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.
Zhou
Ge
G
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Hashimoto
Yoshihiro
Y
Kwak
Inseok
I
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D051548:Histone Acetyltransferases; D006727:Hormone Antagonists / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D011471:Prostatic Neoplasms / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013256:Steroids / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006727:Hormone Antagonists; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D013256:Steroids; D015534:Trans-Activators; D015735:Mifepristone; D051548:Histone Acetyltransferases; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D011494:Protein Kinases; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases