The Y-located proto-oncogene TSPY exacerbates and its X-homologue TSPX inhibits transactivation functions of androgen receptor and its constitutively active variants.
The 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.
Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center.|Institute for Human Genetics, University of California, San Francisco, CA 94121, USA.
Yunmin
Y
Li
Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center.|Institute for Human Genetics, University of California, San Francisco, CA 94121, USA.
Dong Ji
DJ
Zhang
Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Yun
Y
Qiu
Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center.|Institute for Human Genetics, University of California, San Francisco, CA 94121, USA.
Tatsuo
T
Kido
Division of Cell and Developmental Genetics, Department of Medicine, VA Medical Center.|Institute for Human Genetics, University of California, San Francisco, CA 94121, USA.
Yun-Fai Chris
YC
Lau
D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000235:genetics; D041322:Chromosomes, Human, Y / Q000235:genetics; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D018238:Gonadoblastoma / Q000235:genetics; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D000072417:Protein Domains / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D013737:Testis / Q000254:growth & development / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D011944:Receptors, Androgen; C497749:TSPY1 protein, human; C432963:TSPYL2 protein, human