Talk:Y Chromosome

2010

Dual nuclear import mechanisms of sex determining factor SRY: intracellular Ca2+ as a switch

FASEB J. 2010 Nov 4.

Kaur G, Jans DA.

• Nuclear Signalling Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia; and.

Abstract

The sex-determining region on the Y chromosome (SRY) has 2 nuclear localization signals (NLSs) that flank the DNA binding high mobility group (HMG) domain; the β-NLS and the CaM-NLS, which mediate nuclear transport through importin β1 (Impβ1) and the calcium-binding protein calmodulin (CaM), respectively. Here we reconstitute the nuclear import mediated by the 2 NLSs for the first time in vitro, establishing Ran independence of CaM-NLS-dependent transport. The β- and CaM-NLSs were found to be independently functional out of the context of the SRY HMG domain, dependent on Impβ1 and CaM binding, respectively. Intriguingly, direct protein binding assays also indicated competitive binding of Impβ1 and CaM to the SRY HMG domain. To assess the potential role of intracellular calcium in modulating SRY nuclear accumulation, Cos-7 cells expressing SRY and control constructs were treated with agents elevating or reducing intracellular Ca(2+) levels. The in vivo results, supported by experiments in vitro where transport was assessed with or without 2 μ M Ca(2+), indicate a Ca(2+)-dependent mode of nuclear transport via the CaM-NLS/CaM, with inhibition of β-NLS/Impβ1-mediated nuclear import by intracellular Ca(2+). The results imply mutual exclusivity of nuclear transport via the 2 NLSs with intracellular Ca(2+) as the switch between the 2.-Kaur, G. Jans, D. A. Dual nuclear import mechanisms of sex determining factor SRY: intracellular Ca(2+) as a switch.

PMID: 21051653

http://www.ncbi.nlm.nih.gov/pubmed/21051653

Testis-specific protein on Y chromosome (TSPY) represses the activity of the androgen receptor in androgen-dependent testicular germ-cell tumors

Proc Natl Acad Sci U S A. 2010 Nov 1.

Akimoto C, Ueda T, Inoue K, Yamaoka I, Sakari M, Obara W, Fujioka T, Nagahara A, Nonomura N, Tsutsumi S, Aburatani H, Miki T, Matsumoto T, Kitagawa H, Kato S.

The Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Abstract

Testis-specific protein on Y chromosome (TSPY) is an ampliconic gene on the Y chromosome, and genetic interaction with gonadoblastoma has been clinically established. However, the function of the TSPY protein remains to be characterized in physiological and pathological settings. In the present study, we observed coexpression of TSPY and the androgen receptor (AR) in testicular germ-cell tumors (TGCTs) in patients as well as in model cell lines, but such coexpression was not seen in normal testis of humans or mice. TSPY was a repressor for androgen signaling because of its trapping of cytosolic AR even in the presence of androgen. Androgen treatment stimulated cell proliferation of a TGCT model cell line, and TSPY potently attenuated androgen-dependent cell growth. Together with the finding that TSPY expression is reduced in more malignant TGCTs in vivo, the present study suggests that TSPY serves as a repressor in androgen-induced tumor development in TGCTs and raises the possibility that TSPY could be used as a clinical marker to assess the malignancy of TGCTs.

PMID: 21041627 http://www.ncbi.nlm.nih.gov/pubmed/21041627