| 저자(한글) |
Lee, Yun Yeong,Ryu, Min Sook,Kim, Hong Seok,Suganuma, Masami,Song, Kye Yong,Lim, In Kyoung |
| 초록 |
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) ${ alpha}$ and $PKC{ beta}1$ exerted differential effects on the nuclear translocation of cytoplasmic pErk1/2, a protein which maintains senescence. $PKC{ alpha}$ 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 $PKC{ alpha}$ were both required for pErk1/2 transport to the nucleus. Repetitive exposure of mouse skin to TPA downregulated $PKC{ alpha}$ expression and increased epidermal and hair follicle cell proliferation. Thus, $PKC{ alpha}$ 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 $PKC{ alpha}$ 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 $PKC{ alpha}$ 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. |
