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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2016.3
- 수록면
- 266 - 279 (14page)
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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) ? and PKC?1 exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. PKC? accompanied pErk1/2 to the nucleus after freeing it from PEA-15pS104 via PKC?1 and then was rapidly ubiquitinated and degraded within the nucleus. Mitogen-activated protein kinase docking motif and kinase activity of PKC? were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated PKC? expression and increased epi-dermal and hair follicle cell proliferation. Thus, PKC? 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? 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? 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.
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참고문헌 (42)
참고문헌 신청
Abel, E. L. / 2009 / Multistage chemical carcinogenesis in mouse skin : fundamentals and applications / Nat. Protoc 4:1350~1362
Alessandrini, A. / 1992 / Phorbol ester stimulates a protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product / Proc. Natl. Acad. Sci. USA 89:8200~8204
Alexandropoulos, K. / 1993 / Ha-Ras functions downstream from protein kinase C in v-Fpsinduced gene expression mediated by TPA response elements / Oncogene 8:803~807
Araujo, H. / 1993 / Characterization of PEA-15, a major substrate for protein kinase C in astrocytes / J. Biol. Chem 268:5911~5920
Ashendel, C. L. / 1985 / The phorbol ester receptor : a phospholipidregulated protein kinase / Biochim. Biophys. Acta 822:219~242
Alessandrini, A. / 1992 / Phorbol ester stimulates a protein-tyrosine/threonine kinase that phosphorylates and activates the Erk-1 gene product / Proc. Natl. Acad. Sci. USA 89:8200~8204
Alexandropoulos, K. / 1993 / Ha-Ras functions downstream from protein kinase C in v-Fpsinduced gene expression mediated by TPA response elements / Oncogene 8:803~807
Araujo, H. / 1993 / Characterization of PEA-15, a major substrate for protein kinase C in astrocytes / J. Biol. Chem 268:5911~5920
Ashendel, C. L. / 1985 / The phorbol ester receptor : a phospholipidregulated protein kinase / Biochim. Biophys. Acta 822:219~242
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