Control of prostate cell growth: BMP antagonizes androgen mitogenic activity with incorporation of MAPK signals in Smad1.
Alterations in the signaling pathways of bone morphogenetic proteins (BMPs) and activation of the ERK/MAP kinase (MAPK) pathway by growth factors have been implicated in the development and progression of prostate cancer. Smad1 acts as a substrate for MAPKs and also performs a central role in transmitting signals from BMPs. We found that BMPs/Smad1 signaling inhibits the growth of androgen-sensitive prostate cancer cells. Upon the incorporation of ERK/MAPK signals at its linker region, Smad1 physically interacts with androgen-activated androgen receptor (AR) and suppresses its functions. BMPs induce the function of Smad1 as an AR transcriptional corepressor. We demonstrated in vivo that Smad1 signaling is low in androgen-regulated growth of prostate cancer, is activated after castration, and also is decreased in hormone-independent tumors. The activation status of ERK/MAPK parallels Smad1 in the progression of prostate cancer; thus, our findings indicate a molecular basis for the integration of signals of MAPK and Smad1 in the progression and androgen regulation of prostate cancer.
Qiu
Tao
T
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Grizzle
William E
WE
Oelschlager
Denise K
DK
Shen
Xing
X
Cao
Xu
X
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008954:Models, Biological; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D019485:Bone Morphogenetic Proteins; D011944:Receptors, Androgen; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D020928:Mitogen-Activated Protein Kinases