SM22α-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of γ-radiation and doxorubicin in HepG2 cells
SM22α-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of γ-radiation and doxorubicin in HepG2 cells
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DOI：
10.1016/j.bbrc.2010.08.018
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发表时间：
2010-09-10
影响因子：
3.1
通讯作者：
Kim, In Gyu
中科院分区：
文献类型：
--
作者：
Kim, Tae Rim;Lee, Hee Min;Kim, In Gyu
平滑肌蛋白22-α（SM 22 α）被认为是一种在平滑肌组织和成纤维细胞中发现的转化和形状变化敏感的肌动蛋白交联蛋白;然而，其功能作用仍然不确定。我们以前报道过SM 22 α过表达通过诱导HepG 2细胞中的金属硫蛋白（MT）同工酶而赋予对抗癌药物或辐射的抗性。在这项研究中，我们证明，SM 22 α过表达导致细胞的生长停滞状态，并促进细胞衰老所造成的治疗与亚临床剂量的γ-辐射（0.05和0.1戈伊）或阿霉素（0.01和0.05 μ g/ml），与对照细胞。已知衰老生长停滞由p53磷酸化/p21（WAF 1/Cip 1）诱导或p16（INK 4a）/视网膜母细胞瘤蛋白（pRB）激活控制。在HepG 2细胞中SM 22 α过表达升高p16（INK 4a），随后激活pRB，但不激活p53/p21（WAF 1/Cip 1）通路。此外，由SM 22 α过表达诱导的MT-1G参与p16（INK 4a）/pRB通路的激活，这导致生长停滞状态并促进由损伤剂引起的细胞衰老。我们的研究结果首次证明，SM 22 α通过调节HepG 2细胞中的p16（INK 4a）/pRB通路来调节由损伤剂引起的细胞衰老，并且SM 22 α的这些作用部分由MT-1G介导。(C)2010年爱思唯尔公司All rights reserved.
Smooth muscle protein 22-alpha (SM22 alpha) 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 SM22 alpha overexpression confers resistance against anticancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22 alpha overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of gamma-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 mu g/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. SM22 alpha 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 SM22 alpha 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 SM22 alpha modulates cellular senescence caused by damaging agents via regulation of the p16(INK4a)/pRB pathway in HepG2 cells and that these effects of SM22 alpha are partially mediated by MT-1G. (C) 2010 Elsevier Inc. All rights reserved.