TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

Abstract

Testis-specific protein Y-encoded (TSPY) is the putative gene for the gonadoblastoma locus on the Y chromosome (GBY). TSPY and an X-homologue, TSPX, harbor a conserved domain, designated as SET/NAP domain, but differ at their C termini. Ectopic expression of TSPY accelerates cell proliferation by abbreviating the G 2 /M stage, whereas overexpression of TSPX retards cells at the same stage of the cell cycle. Previous studies demonstrated that the SET oncoprotein is capable of binding to cyclin B. Using various protein interaction techniques, we demonstrated that TSPY and TSPX indeed bind competitively to cyclin B at their SET/NAP domains in vitro and in vivo. TSPY colocalizes with cyclin B1 during the cell cycle, particularly on the mitotic spindles at metaphase. TSPY enhances while TSPX represses the cyclin B1-CDK1 phosphorylation activity. The inhibitory effect of TSPX on the cyclin B1-CDK1 complex has been mapped to its carboxyl acidic domain that is absent in TSPY, suggesting that TSPX could serve a normal function in modulating cell-cycle progression at the G 2 /M stage, whereas TSPY has acquired a specialized function in germ cell renewal and differentiation. Epigenetic dysregulation of TSPY in incompatible germ or somatic cells could promote cell proliferation and predispose susceptible cells to tumorigenesis.

Sex disparities in melanoma outcomes: The role of biology

“…It plays a role in cell cycle regulation by interacting with cyclin B-CDK1 complex, stimulating its kinase activities and accelerating G2/M transition of the host cells [135,136]. In addition, it also binds the translation elongation factor eEF1A and promotes cellular protein synthesis [137].…”

“…Decreased B cell activation, differentiation and survival [64] Low CD 3 + T lymphocytes [53] Increased T cell apoptosis [151] Low IL2 and TH1 responses and thus suppression of T and B-lymphocytes development [53] Oxidative processes -Decreased oxidative damage to mitochondrial DNA [82] -Estrogen protects cells against oxidative stress and acts as a direct antioxidant [82] -High level of anti-oxidant enzymes [86] -High oxidative damage to mitochondrial DNA (4-fold higher compared with women) [82] -Androgens diminish protection against oxidative stress [85] -Decreased number of anti-oxidants and anti-oxidant enzymes [86] -Elevated ROS cellular environment promote tumor metastasis [75,86,87] Sex chromosomes -X chromosome inactivation process: [55,108,109] Decreased tissue X chromosome oncogenes expression [mi-RNAs, cancer/testis antigens (CT-X)] [117][118][119][120][121] Tissue mosaicism in X chromosome associated oncogenes -Lack of Y chromosome associated oncogenes -No X chromosome inactivation process: [55,108,109] Monosomic expression of X chromosome specific oncogenes Increased tissue expression of X chromosome oncogenes -Y chromosome associated oncogene expression [TSPY] [133][134][135][136]139] DNA binding sites to elicit transcriptional regulation of target genes. Studies from androgen receptor knockout mouse models demonstrate that androgens influence the promotion of tumorigenesis in liver and prostate cancer and promote both tumorigenesis and metastasis in bladder, lung, kidney cancers [43], which have sex disparities in outcome favoring women (Table 1, Supplemental Fig.…”

Testis-Specific Protein Y-Encoded Copy Number Is Correlated to Its Expression and the Field Fertility of Canadian Holstein Bulls

“…The exact function of TSPY remains unknown; however, it has been linked to both spermatogonial proliferation and meiosis [Schnieders et al, 1996;Vogel et al, 1997]. More specifically, it has been associated with cell cycle acceleration and with the regulation of androgen receptor [Oram et al, 2006;Li and Lau, 2008;Akimoto et al, 2010].…”

TSPY1 (testis specific protein, Y-linked 1)

“…It was later shown in transiently transfected HeLa and HEK293 cells that this effect is mediated by a direct interaction of the SET/NAP domain of TSPY with the activated cyclin B1/CDK complex. TSPY accelerates the G2/M-phase transition of host cells by stimulating the kinase activity of the activated cyclin B1/CDK complex (Li et al, 2008). The co-localization of TSPY and cyclin B1 in spermatogonia and primary spermatocytes suggests a putative interaction of both proteins during spermatogonial renewal and during the prophase I of the first meiotic division .…”

“…TSPY-L occurs mainly as a phosphoprotein with a predicted size of 38 kDa (Schnieders et al, 1996). TSPY is sharing with its Xencoded homolog TSPYL2 (designated also as TSPX, CDA1, DENTT or NP79), autosomal TSPY-like paralogs and with SET and NAP-1 a highly-conserved type B cyclin binding SET/NAP domain (amino acids residues 121-265 according to Li and Lau, 2008). For human TSPY the translation elongation factor eEF1A1 has also been identified as binding partner of the SET/NAP domain in a yeast-two-hybrid screen (Kido and Lau, 2008).…”