Reactive oxygen species-mediated cyclin D1 degradation mediates tumor growth retardation in hypoxia, independently of p21cip1 and hypoxia-inducible factor.
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)-1alpha 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 -2alpha 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.
Lim
Ji-Hong
JH
Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Lee
Yoon-Mi
YM
Chun
Yang-Sook
YS
Park
Jong-Wan
JW
D002453:Cell Cycle / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D019938:Cyclin D1