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KMID : 0578320160390030266
Molecules and Cells
2016 Volume.39 No. 3 p.266 ~ p.279
Regulations of Reversal of Senescence by PKC Isozymes in Response to 12-O-Tetradecanoylphorbol-13-Acetate via Nuclear Translocation of pErk1/2
Lee Yun-Yeong

Ryu Min-Sook
Kim Hong-Seok
Suganuma Masami
Song Kye-Yong
Lim In-Kyoung
Abstract
The mechanism by which 12-O-tetradecanoylphorbol-13-acetate (TPA) bypasses cellular senescence was investigated using human diploid fibroblast (HDF) cell replicative senescence as a model. Upon TPA treatment, protein kinase C (PKC) ¥á and PKC¥â1 exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. PKC¥á accompanied pErk1/2 to the nucleus after freeing it from PEA-15pS104via PKC¥â1 and then was rapidly ubiquitinated and degraded within the nucleus. Mitogen-activated protein kinase docking motif and kinase activity of PKC¥á were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated PKC¥á expression and increased epidermal and hair follicle cell proliferation. Thus, PKC¥á downregulation is accompanied by in vivo cell proliferation, as evidenced in 7, 12-dimethylbenz(a)anthracene (DMBA)-TPA-mediated carcinogenesis. The ability of TPA to reverse senescence was further demonstrated in old HDF cells using RNA-sequencing analyses in which TPA-induced nuclear PKC¥á degradation freed nuclear pErk1/2 to induce cell proliferation and facilitated the recovery of mitochondrial energy metabolism. Our data indicate that TPA-induced senescence reversal and carcinogenesis promotion share the same molecular pathway. Loss of PKC¥á expression following TPA treatment reduces pErk1/2-activated SP1 biding to the p21WAF1 gene promoter, thus preventing senescence onset and overcoming G1/S cell cycle arrest in senescent cells.
KEYWORD
HDF, PKC¥á, PKC¥â1, SA-pErk1/2, tumor promotion
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