Distinct nuclear and cytoplasmic functions of androgen receptor cofactor p44 and association with androgen-independent prostate cancer.
Androgen receptor (AR) mediates transcriptional activation of diverse target genes through interactions with various coactivators that may alter its function and help mediate the switch between prostate cell proliferation and differentiation. We recently identified p44/MEP50 as an AR coactivator and further showed that it is expressed primarily in the nucleus and cytoplasm of benign prostate epithelial and prostate cancer cells, respectively. We also showed that haploinsufficiency in p44(+/-) mice causes prostate epithelial cell proliferation. To establish direct cause-and-effect relationships, we have used p44 fusion proteins that are selectively expressed in the nucleus or cytoplasm of prostate cancer cells (LNCaP), along with RNAi analyses, to examine effects of p44 both in vitro and in vivo (in tumor xenografts). We show that preferential expression of p44 in the nucleus inhibits proliferation of LNCaP cells in an AR-dependent manner, whereas preferential expression of p44 in the cytoplasm enhances cell proliferation. These effects appear to be mediated, at least in part, through the regulation of distinct cell-cycle regulatory genes that include p21 (up-regulated by nuclear p44) and cyclin D2 and CDK6 (up-regulated by cytoplasmic p44). Importantly, we also demonstrate that altered p44 expression is associated with androgen-independent prostate cancer. Our results indicate that nuclear p44 and cytoplasmic p44 have distinct and opposing functions in the regulation of prostate cancer cell proliferation.
Peng
Yi
Y
Departments of Pathology and Microbiology, New York University School of Medicine, New York, NY 10010, USA.
Chen
Fei
F
Melamed
Jonathan
J
Chiriboga
Luis
L
Wei
Jianjun
J
Kong
Xiangtian
X
McLeod
Maureen
M
Li
Yirong
Y
Li
Caihong X
CX
Feng
Alice
A
Garabedian
Michael J
MJ
Wang
Zhengxin
Z
Roeder
Robert G
RG
Lee
Peng
P
D000728:Androgens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D056742:Cyclin D2; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D011944:Receptors, Androgen; D014157:Transcription Factors; C478359:WDR77 protein, human; D051361:Cyclin-Dependent Kinase 6