Multifunction steroid receptor coactivator, E6-associated protein, is involved in development of the prostate gland.
In this study we report that deletion of E6-associated protein (E6-AP) in mice results in a smaller prostate gland compared with that in normal wild-type animals. To investigate the mechanism(s) by which E6-AP affects prostate gland growth and development, we carried out both in vitro and in vivo experiments. In this study we show that E6-AP interacts with androgen receptor (AR) in a hormone-dependent manner and enhances the transactivation function of AR. Our in vivo data from E6-AP-null prostate glands show that the level of AR protein is elevated while the level of the AR target protein, probasin, is decreased. In contrast, the level of AR protein is decreased, and its target protein is increased in an E6-AP-overexpressing stable cell line, suggesting that E6-AP modulates both the protein level and the activity of AR. In addition, we show that the levels of phosphatidylinositol 3-kinase, total Akt, and phosphorylated Akt are decreased in E6-AP-null prostate, suggesting that E6-AP deletion down-regulates the signaling of the phosphatidylinositol 3-kinase-Akt pathway. We also show that RhoA negatively regulates AR function, and RhoA levels are increased in E6-AP-null prostate. Furthermore, expression levels of p53, Bax, active caspases, and apoptotic index are increased in E6-AP-null prostate. Collectively, our data suggest that E6-AP deletion attenuates the growth and development of the prostate gland by interfering with AR function as well as by stimulating p53-mediated apoptosis.
Khan
Obaid Y
OY
Department of Biochemistry and Molecular Biology, Braman Breast Cancer Institute (M-877), University of Miami Miller School of Medicine, Batchelor's Building, Room 416, 1580 Northwest 10 Avenue, Miami, Florida 33136, USA.
Fu
Guilian
G
Ismail
Ayesha
A
Srinivasan
Sathish
S
Cao
Xuni
X
Tu
Yaping
Y
Lu
Shan
S
Nawaz
Zafar
Z
D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000254:growth & development* / Q000473:pathology / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D000727:Androgen-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C027519:probasin; D013739:Testosterone; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D020742:rhoA GTP-Binding Protein