CSIG inhibits PTEN translation in replicative senescence
CSIG inhibits PTEN translation in replicative senescence
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CSIG 抑制复制衰老中的 PTEN 翻译
DOI：
10.1128/mcb.00142-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
--
作者：
Ma, Liwei;Chang, Na;Tong, Tanjun
使用抑制性消减杂交系统，我们鉴定了CSIG(细胞衰老抑制基因蛋白；RSL1D1)，它在年轻的人二倍体成纤维细胞中含量丰富，但随着复制衰老而减弱。CSIG的过表达或下调不影响p21(Cip1)和p16(INK4a)的表达。相反，CSIG负调控PTEN和p27(Kip1)的表达，进而促进细胞增殖。在PTEN沉默的HEK 293细胞和PTEN缺陷型人胶质母细胞瘤U87 MG细胞中，CSIG对p27(Kip1)表达和细胞分裂的影响被取消，提示CSIG对p27(Kip1)的调节和细胞周期的进展需要PTEN。对其潜在机制的研究表明，CSIG对PTEN的调控是通过翻译抑制机制实现的。进一步的研究表明，CSIG与PTEN基因在5‘非翻译区相互作用，并且CSIG的敲除导致PTEN 5’非翻译区-荧光素酶报告基因的荧光素酶活性增加。此外，CSIG的过表达显著延缓了复制衰老的进程，而下调CSIG的表达则加速了复制衰老。PTEN基因敲除可减弱CSIG对细胞衰老的影响。我们的发现表明，CSIG是复制衰老的一个新的调节成分，它需要PTEN作为中介，并参与翻译调节机制。
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 p21(Cip1) and p16(INK4a) expressions. Instead, CSIG negatively regulated PTEN and p27(Kip1) expressions, 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 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.