SM22α-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of γ-radiation and doxorubicin in HepG2 cells.
Smooth muscle protein 22-alpha (SM22α) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22α overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22α overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of γ-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 μg/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21(WAF1/Cip1) induction or p16(INK4a)/retinoblastoma protein (pRB) activation. SM22α overexpression in HepG2 cells elevated p16(INK4a) followed by pRB activation, but did not activate the p53/p21(WAF1/Cip1) pathway. Moreover, MT-1G, which is induced by SM22α overexpression, was involved in the activation of the p16(INK4a)/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22α modulates cellular senescence caused by damaging agents via regulation of the p16(INK4a)/pRB pathway in HepG2 cells and that these effects of SM22α are partially mediated by MT-1G.
Kim
Tae Rim
TR
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Republic of Korea.
Lee
Hee Min
HM
Lee
So Yong
SY
Kim
Eun Jin
EJ
Kim
Kug Chan
KC
Paik
Sang Gi
SG
Cho
Eun Wie
EW
Kim
In Gyu
IG
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D005720:Gamma Rays; D006801:Humans; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; C499629:MT1G protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins; D016160:Retinoblastoma Protein; C051615:transgelin; D004317:Doxorubicin; D008668:Metallothionein