CSIG inhibits PTEN translation in replicative senescence.
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.
Ma
Liwei
L
Research Center on Aging, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, People's Republic of China.
Chang
Na
N
Guo
Shuzhen
S
Li
Qian
Q
Zhang
Zongyu
Z
Wang
Wengong
W
Tong
Tanjun
T
D020121:5' Untranslated Regions / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D011257:Pregnancy Proteins / Q000378:metabolism*; D011485:Protein Binding; D014176:Protein Biosynthesis; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
D020121:5' Untranslated Regions; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C117409:RSL1D1 protein, human; D012269:Ribosomal Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human