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Gonadoblastoma locus and the TSPY gene on the human Y chromosome.

The gonadoblastoma (GBY) locus is the only oncogenic locus on the human Y chromosome. It is postulated to serve a normal function in the testis, but could exert oncogenic effects in dysgenetic gonads of individuals with intersex and/or dysfunctional testicular phenotypes. Recent studies establish the testis-specific protein Y-encoded (TSPY) gene to be the putative gene for GBY. TSPY serves normal functions in male stem germ cell proliferation and differentiation, but is ectopically expressed in early and late stages of gonadoblastomas, testicular carcinoma in situ (the premalignant precursor for all testicular germ cell tumors), seminomas, and selected nonseminomas. Aberrant TSPY expression stimulates protein synthetic activities, accelerates cell proliferation, and promotes tumorigenicity in athymic mice. TSPY binds to type B cyclins, enhances an activated cyclin B-CDK1 kinase activity, and propels a rapid G(2)/M transition in the cell cycle. TSPY also counteracts the normal functions of its X-homologue, TSPX, which also binds to cyclin B and modulates the cyclin B-CDK1 activity to insure a proper G(2)/M transition in the cell cycle. Hence, ectopic expression and actions of the Y-located TSPY gene in incompatible germ cells, such as those in dysgenetic or ovarian environments and dysfunctional testis, disrupt the normal cell cycle regulation and predispose the host cells to tumorigenesis. The contrasting properties of TSPY and TSPX suggest that somatic cancers, such as intracranial germ cell tumors, melanoma, and hepatocellular carcinoma, with detectable TSPY expression could exhibit sexual dimorphisms in the initiation and/or progression of the respective oncogenesis.

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