Mechanisms of c-Myc Degradation by Nickel Compounds and Hypoxia 英文参考文献.docVIP

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Mechanisms of c-Myc Degradation by Nickel Compounds and Hypoxia 英文参考文献.doc

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Mechanisms of c-Myc Degradation by Nickel Compounds and Hypoxia 英文参考文献

Mechanismsofc-MycDegradationbyNickelCompounds andHypoxia QinLi,ThomasKluz,HongSun,MaxCosta* DepartmentofEnvironmentalMedicine,NewYorkUniversitySchoolofMedicine,Tuxedo,NewYork,UnitedStatesofAmerica Abstract Nickel (Ni) compounds have been found to cause cancer in humans and animal models and to transform cells in culture. At least part of this effect is mediated bystabilization of hypoxia inducible factor (HIF1a) and activating its downstream signaling. Recent studies reported that hypoxia signaling might either antagonize or enhance c-myc activity depending on cell context. We investigated the effect of nickel on c-myc levels, and demonstrated that nickel, hypoxia, andother hypoxia mimetics degraded c-myc protein inanumber ofcancer cells (A549, MCF-7, MDA- 453, and BT-474). The degradation of the c-Myc protein was mediated by the 26S proteosome. Interestingly, knockdown ofboth HIF-1aandHIF-2aattenuated c-Myc degradation induced byNickel andhypoxia, suggesting the functional HIF-1aand HIF-2awas required for c-myc degradation. Further studies revealed two potential pathways mediated nickel and hypoxia induced c-myc degradation. Phosphorylation of c-myc at T58 was significantly increased incells exposed tonickel orhypoxia, leading toincreased ubiquitination through Fbw7 ubiquitin ligase. In addition, nickel andhypoxia exposure decreased USP28,ac-myc de-ubiquitinating enzyme, contributing toahigher steady state level of c-myc ubiquitination and promoting c-myc degradation. Furthermore, the reduction of USP28 protein by hypoxia signaling is due to both protein degradation and transcriptional repression. Nickel and hypoxia exposure significantly increased the levels of dimethylated H3 lysine 9 at the USP28 promoter and repressed its expression. Our study demonstrated that Nickel and hypoxia exposure increased c-myc T58 phosphorylation and decreased USP28 protein levels incancer cells, which both lead toenhanced c-myc ubiquitination and proteasomal degradation. Ci