Song Lun, Dong Wen, Gao Ming, Li Jingxia, Hu Meiru, Guo Ning, Huang Chuanshu
Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, People's Republic of China.
Biochim Biophys Acta. 2010 Feb;1803(2):323-32. doi: 10.1016/j.bbamcr.2010.01.006. Epub 2010 Jan 15.
Exposure to ultraviolet B (UVB) irradiation (290-320nm wavelength) from sunlight induces a variety of medical problems, including sunburn, immunosuppression and skin cancers. However, the molecular mechanisms related to UVB-induced cell damage and/or mutagenic effects have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IkappaB kinase complex (IKK), IKKalpha, plays a critical role in mediation of the UVB-induced G0/G1 cell cycle arrest response by suppressing Cyclin D1 expression. Notably, IKKa-dependent Cyclin D1 regulation is unrelated to IKKbeta/NF-kappaB activity. We further show that IKKalpha-dependent downregulation of Cyclin D1 expression in the UVB response results from the reduction of ERK1/2-dependent Cyclin D1 transcription coupled with an increase of p38 kinase-dependent Cyclin D1 proteolysis. Thus, our results have identified the novel role of IKKalpha in regulating cell cycle progression during the cellular UVB response. Targeting IKKalpha might be promising for the prevention of UVB-induced cell damage and tumorigenic effects.
暴露于阳光中的紫外线B（UVB）辐射（波长290 - 320nm）会引发多种医学问题，包括晒伤、免疫抑制和皮肤癌。然而，与UVB诱导的细胞损伤和/或诱变效应相关的分子机制尚未完全明确。在此，我们证明IκB激酶复合物（IKK）的催化亚基之一IKKα，通过抑制细胞周期蛋白D1的表达，在介导UVB诱导的G0/G1细胞周期停滞反应中起关键作用。值得注意的是，IKKα依赖的细胞周期蛋白D1调节与IKKβ/NF-κB活性无关。我们进一步表明，UVB反应中IKKα依赖的细胞周期蛋白D1表达下调是由于ERK1/2依赖的细胞周期蛋白D1转录减少以及p38激酶依赖的细胞周期蛋白D1蛋白水解增加所致。因此，我们的研究结果确定了IKKα在细胞UVB反应过程中调节细胞周期进程的新作用。靶向IKKα可能对预防UVB诱导的细胞损伤和致瘤效应具有前景。
