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Mol. Cell. Biol. doi:10.1128/MCB.00142-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CSIG Inhibits PTEN Translation in Replicative Senescence

Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, P. R. China

^* To whom correspondence should be addressed. Email: wwg{at}bjmu.edu.cn. tztong{at}bjmu.edu.cn.

	Abstract

Using a suppressive subtractive hybridization system, we identified a Cellular Senescence-Inhibited Gene (CSIG/RSL1D1) that was abundant in young human diploid fibroblast cells but declined upon replicative senescence. Over-expression or knock-down of CSIG did not influence p21^Cip1 and p16^INK4a expression. Instead, CSIG negatively regulated PTEN and p27^Kip1 expression, in turn promoting cell proliferation. In PTEN-silenced HEK 293 cells and PTEN-deficient human glioblastoma U87MG cells, the effect of CSIG on p27^Kip1 expression and cell division was abolished, suggesting that PTEN was required for the role of CSIG on p27^Kip1 regulation and cell cycle progression. Investigation into the mechanism underlying revealed that the regulation of PTEN by CSIG was achieved through a translational suppression mechanism. Further study showed that CSIG interacted with PTEN mRNA in the 5' UTR and that knock-down of CSIG led to increased luciferase activity of a PTEN 5' UTR-luciferase reporter. Moreover, over-expression of CSIG significantly delayed the progression of replicative senescence, while knock-down of CSIG expression accelerated replicative senescence. Knock-down of PTEN diminished the effect of CSIG on cellular senescence. Our findings indicate that CSIG acts as a novel regulatory component of replicative senescence, which requires PTEN as a mediator and involves in a translational regulatory mechanism.