The SRC-3/AIB1 coactivator is degraded in a ubiquitin- and ATP-independent manner by the REGgamma proteasome.
Steroid receptor coactivator-3 (SRC-3/AIB1) is an oncogene frequently amplified and overexpressed in breast cancers. Here we report that SRC-3 interacts with REGgamma, a proteasome activator known to stimulate the trypsin-like activity of the 20S proteasome. RNAi knockdown and gain-of-function experiments suggest that REGgamma promotes SRC-3 protein degradation. Cellular levels of REGgamma expression affect estrogen-receptor target-gene expression and cell growth as a result of its ability to promote degradation of the SRC-3 protein. In vitro proteasome proteolysis assays using purified REGgamma, SRC-3, and the 20S proteasome reinforce these conclusions and demonstrate that REGgamma promotes the degradation of SRC-3 in a ubiquitin- and ATP-independent manner. This work demonstrates the first example of a physiologically relevant endogenous cellular target for the REGgamma-proteasome complex. It also highlights the fact that an alternative mode of proteasome-mediated protein degradation, independent of the 19S proteasome regulatory cap, targets the SRC-3 protein for degradation.
Li
Xiaotao
X
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Lonard
David M
DM
Jung
Sung Yun
SY
Malovannaya
Anna
A
Feng
Qin
Q
Qin
Jun
J
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
O'Malley
Bert W
BW
D000123:Acetyltransferases / Q000187:drug effects / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001324:Autoantigens / Q000378:metabolism* / Q000494:pharmacology; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation
D001324:Autoantigens; C099558:Ki antigen; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D015534:Trans-Activators; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; D046988:Proteasome Endopeptidase Complex