Reactive oxygen species-mediated cyclin D1 degradation mediates tumor growth retardation in hypoxia, independently of p21cip1 and hypoxia-inducible factor
Reactive oxygen species-mediated cyclin D1 degradation mediates tumor growth retardation in hypoxia, independently of p21cip1 and hypoxia-inducible factor
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DOI：
10.1111/j.1349-7006.2008.00892.x
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发表时间：
2008-09-01
期刊：
影响因子：
5.7
通讯作者：
Park, Jong-Wan
中科院分区：
文献类型：
--
作者：
Lim, Ji-Hong;Lee, Yoon-Mi;Park, Jong-Wan
细胞生长停滞是肿瘤在缺氧环境中生存的一种适应过程。由于增殖是一个非常复杂和动态的过程，缺氧生长停滞不被认为是简单地由几个分子决定的。最近，一些研究小组已经证明，缺氧诱导因子（HIF）-1 α通过抑制c-Myc和随后诱导p21（cip 1）表达在缺氧诱导的细胞周期阻滞中起着至关重要的作用。然而，我们发现，缺氧生长停滞甚至可以发生在p21-null癌细胞，并解决了p21-独立的细胞周期停滞的过程。我们发现，细胞周期蛋白D1在各种癌细胞系在缺氧条件下下调，这是独立的p21和HIF-1和-2 α的表达。同时发现，细胞周期蛋白D1被泛素-蛋白酶体系统破坏稳定，并且这种降解过程被缺氧高度激活。此外，抗氧化剂防止缺氧降解的细胞周期蛋白D1和过氧化氢不稳定的细胞周期蛋白D1在常氧。最后，我们证明了细胞周期蛋白D1的异位表达在p21（+/+）和p21（-/-）HCT 116细胞中挽救了缺氧生长停滞。鉴于这些结果，我们在这里提出，活性氧介导的细胞周期蛋白D1降解有助于肿瘤生长迟缓在缺氧环境中。
Cell growth arrest is an adaptation process for tumor survival in hypoxic environments. As proliferation is a very complicated and dynamic process, hypoxic growth arrest is not considered to be simply determined by a few molecules. Recently, several research groups have demonstrated that hypoxia-inducible factor (HIF)-1 alpha plays a crucial role in hypoxia-induced cell-cycle arrest by inhibiting c-Myc and subsequently inducing p21(cip1) expression. However, we found that hypoxic growth arrest could occur even in p21-null cancer cells, and addressed the p21-independent process of cell-cycle arrest. We show that cyclin D1 was downregulated in various cancer cell lines under hypoxic conditions, which was independent of p21 and HIF-1 and -2 alpha expression. It was also found that cyclin D1 was destabilized by the ubiquitin-proteasome system and this degradation process was highly activated by hypoxia. Moreover, antioxidants prevented the hypoxic degradation of cyclin D1 and hydrogen peroxide destabilized cyclin D1 in normoxia. Finally, we demonstrated that ectopic expression of cyclin D1 rescued hypoxic growth arrest in both p21(+/+) and p21(-/-) HCT116 cells. Given the results, we here propose that reactive oxygen species-mediated cyclin D1 degradation contributes to tumor growth retardation in hypoxic environments.