The Y-located proto-oncogene TSPY exacerbates and its X-homologue TSPX inhibits transactivation functions of androgen receptor and its constitutively active variants
JournalHuman Molecular Genetics
PublisherOxford University Press
MetadataShow full item record
AbstractThe gonadoblastoma gene, testis-specific protein Y-encoded (TSPY), on the Y chromosome and its X-homologue, TSPX, are cell cycle regulators and function as a proto-oncogene and a tumor suppressor respectively in human oncogenesis. TSPY and TSPX competitively bind to the androgen receptor (AR) and AR variants, such as AR-V7, at their conserved SET/NAP domain, and exacerbate and repress the transactivation of the AR/AR-V7 target genes in ligand dependent and independent manners respectively. The inhibitory domain has been mapped to the carboxyl acidic domain of TSPX, truncation of which renders TSPX to be stimulatory while its transposition to the C-terminus of TSPY results in an inhibitory hybrid protein. TSPY and TSPX co-localize with the endogenous AR, in the presence of ligand, on the promoters and differentially regulate the expression of the endogenous AR target genes in the androgen-responsive LNCaP prostate cancer cells. Transcriptome analysis shows that TSPY and TSPX expressions differentially affect significant numbers of canonical pathways, upstream regulators and cellular functions. Significantly, among the common ones, TSPY activates and TSPX inhibits numerous growth-related and oncogenic canonical pathways and cellular functions in the respective cell populations. Hence, TSPY and TSPX exert opposing effects on the transactivation functions of AR and AR-Vs important for various physiological and disease processes sensitive to male sex hormone actions, thereby not only affecting the pathogenesis of male-specific prostate cancer but also likely contributing to sex differences in the health and diseases of man. Copyright The Author 2017.
SponsorsWe thank Drs Keith Yamamoto and Robert Matusik for providing the androgen receptor plasmids and ARR2PB promoter construct, respectively. National Institutes of Health (grant 1R21 CA152589); Meritreviewed grant 1I01BX000865 from the Department of Veterans Affairs to Y.-F.C.L. Y.-F.C.L. is a Research Career Scientist of the Department of Veterans Affairs.
Cell Cycle Proteins--genetics
Chromosomes, Human, X--genetics
Chromosomes, Human, Y--genetics
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85019128007&doi=10.1093%2fhmg%2fddx005&partnerID=40&md5=18e139b035e72c3e1fec88022cdf5139; http://hdl.handle.net/10713/11303