Regulations of Reversal of Senescence by PKC Isozymes in Response to 12-O-Tetradecanoylphorbol-13-Acetate via Nuclear Translocation of pErk1/2
- Authors
- Lee, Yun Yeong; Ryu, Min Sook; Kim, Hong Seok; Suganuma, Masami; Song, Kye Yong; Lim, In Kyoung
- Issue Date
- Mar-2016
- Publisher
- KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
- Keywords
- HDF; PKC alpha; PKC beta 1; SA-pErk1/2; tumor promotion
- Citation
- MOLECULES AND CELLS, v.39, no.3, pp 266 - 279
- Pages
- 14
- Journal Title
- MOLECULES AND CELLS
- Volume
- 39
- Number
- 3
- Start Page
- 266
- End Page
- 279
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/64306
- DOI
- 10.14348/molcells.2016.2362
- ISSN
- 1016-8478
0219-1032
- 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) a and PKC beta 1 exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. PKCa accompanied pErk1/2 to the nucleus after freeing it from PEA-15pS 104 via PKC beta 1 and then was rapidly ubiquitinated and degraded within the nucleus. Mitogen-activated protein kinase docking motif and kinase activity of PKCa were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated PKCa expression and increased epidermal and hair follicle cell proliferation. Thus, PKCa 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 PKCa 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 PKCa expression following TPA treatment reduces pErk1/2activated SP1 biding to the p21 WAF1 gene promoter, thus preventing senescence onset and overcoming G1/S cell cycle arrest in senescent cells.
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