Downregulation of PEA-15 reverses G1 arrest, and nuclear and chromatin changes of senescence phenotype via pErk1/2 translocation to nuclei

Cellular Signalling
Yun Yeong LeeIn Kyoung Lim

Abstract

We previously showed that senescent cells respond to TPA with translocation of senescence associated-pErk1/2 (SA-pErk1/2) into nuclei along with reversal of senescence morphology. Here, we describe that the reversal of senescence phenotype was manifested by knockdown of cytoplasmic PEA-15 expression, a sequestrator of cytoplasmic pErk1/2. Transfection of short-interfering RNA to PEA-15 (siPEA-15) significantly induced nuclear translocation of SA-pErk1/2, and siPEA-15 with TPA co-treatment further increased the translocation. Moreover, the reversal of senescence phenotype, such as expressions of SA-β-galactosidase, p53, p21(WAF1), PML body, 53BP1 and H3K9me2, was modified by either knockdown of PEA-15 or TPA treatment, indicating that nuclear translocation of SA-pErk1/2 might inhibit senescence progression. Indeed, knockdown of PEA-15 or TPA treatment significantly induced progression of G1 arrested cells to S-phase in human diploid fibroblast (HDF) senescent cells, examined by immunocytochemistry, FACS and immunoblot analyses. In conclusion, downregulation of PEA-15 expression reverses senescence phenotypes via nuclear translocation of SA-pErk1/2, which suggests in vivo maintenance of senescence phenotype by sequestration of pE...Continue Reading

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