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Molecular and Cellular Biology, October 2008, p. 6290-6301, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00142-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

CSIG Inhibits PTEN Translation in Replicative Senescence{triangledown}

Liwei Ma, Na Chang, Shuzhen Guo,{dagger} Qian Li, Zongyu Zhang, Wengong Wang,* and Tanjun Tong*

Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, People's Republic of China

Received 27 January 2008/ Returned for modification 14 March 2008/ Accepted 24 July 2008

Using a suppressive subtractive hybridization system, we identified CSIG (cellular senescence-inhibited gene protein; RSL1D1) that was abundant in young human diploid fibroblast cells but declined upon replicative senescence. Overexpression or knockdown of CSIG did not influence p21Cip1 and p16INK4a expressions. Instead, CSIG negatively regulated PTEN and p27Kip1 expressions, in turn promoting cell proliferation. In PTEN-silenced HEK 293 cells and PTEN-deficient human glioblastoma U87MG cells, the effect of CSIG on p27Kip1 expression and cell division was abolished, suggesting that PTEN was required for the role of CSIG on p27Kip1 regulation and cell cycle progression. Investigation into the underlying mechanism 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' untranslated region (UTR) and that knockdown of CSIG led to increased luciferase activity of a PTEN 5' UTR-luciferase reporter. Moreover, overexpression of CSIG significantly delayed the progression of replicative senescence, while knockdown of CSIG expression accelerated replicative senescence. Knockdown 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.

* Corresponding author. Mailing address: Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100083, People's Republic of China. Phone and fax for Tanjun Tong: 8610-82802931. E-mail: tztong{at}bjmu.edu.cn. Phone and fax for Wengong Wang: 8610-82802949. E-mail: wwg{at}bjmu.edu.cn

{triangledown} Published ahead of print on 4 August 2008.

{dagger} Present address: Neuroprotection Research Lab, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA 02129.

Molecular and Cellular Biology, October 2008, p. 6290-6301, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00142-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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