title: Regulations of Reversal of Senescence by PKC Isozymes in Response to 12-O-Tetradecanoylphorbol-13-Acetate via Nuclear Translocation of pErk1/2.
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) α and PKCβ1 exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. PKCα accompanied pErk1/2 to the nucleus after freeing it from PEA-15pS(104) via PKCβ1 and then was rapidly ubiquitinated and degraded within the nucleus. Mitogen-activated protein kinase docking motif and kinase activity of PKCα were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated PKCα expression and increased epidermal and hair follicle cell proliferation. Thus, PKCα 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 PKCα 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 PKCα expression following TPA treatment reduces pErk1/2-activated SP1 biding to the p21(WAF1) gene promoter, thus preventing senescence onset and overcoming G1/S cell cycle arrest in senescent cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Yun Yeong
authors.initials: YY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Min Sook
authors.initials: MS
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Suganuma
authors.affiliation: Department of Pathology, Chung-Ang University College of Medicine, Seoul 156-756, Korea.
authors.forename: Kye Yong
authors.initials: KY
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Lim
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D064546:Protein Kinase C beta / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; C496628:PRKCA protein, human; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate
keywords: HDF; PKCα; PKCβ1; SA-pErk1/2; tumor promotion