title: cGMP-dependent protein kinase Iβ interacts with p44/WDR77 to regulate androgen receptor-driven gene expression.
abstract: The androgen receptor (AR) pathway plays critical roles in controlling differentiation and proliferation of prostate epithelial cells. We previously identified a novel AR cofactor, p44/WDR77, which specifically enhances AR transcriptional activity in the prostate gland and prostate cancer. To further elucidate p44/WDR77's role in the AR signaling pathway, we conducted a yeast two-hybrid screening and identified cGMP-dependent protein kinase (PKG) as a p44/WDR77-interacting protein. Further investigation by lusiferase assay and kinase assay demonstrated that PKG-Iβ physically interacted with and phosphorylated both p44 and AR and enhanced AR transactivity in synergy with p44 in an androgen- and cGMP-dependent manner. Furthermore, PKG1β expression promoted p44/WDR77 nuclear translocation and inhibited prostate cancer cell growth via G1 cell cycle arrest. Our findings characterize PKG as a novel regulator of AR-mediated transcription by enhancing AR cofactor p44/WDR77's function, which provide a novel mechanism for the growth regulation of prostate cancer cells by the androgen signaling.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Liran
authors.initials: L
authors.lastname: Zhou
authors.forename: Keiko
authors.initials: K
authors.lastname: Hosohata
authors.forename: Shen
authors.initials: S
authors.lastname: Gao
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Gu
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000254:growth & development / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011944:Receptors, Androgen / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: C410798:AR protein, human; D010446:Peptide Fragments; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C478359:WDR77 protein, human; C503486:WDR77 protein, mouse; D062965:Cyclic GMP-Dependent Protein Kinase Type I