Mechanisms of c-Myc Degradation by Nickel Compounds and Hypoxia

• DOI: 10.1371/journal.pone.0008531
• Publication Date: 2009-12-30T21:19:40Z
• Authors: Qin Li; Thomas Kluz; Hong Sun; Max Costa
• Keywords: Hypoxia; Degradation

Nickel (Ni) compounds have been found to cause cancer in humans and animal models transform cells culture. At least part of this effect is mediated by stabilization hypoxia inducible factor (HIF1a) activating its downstream signaling. Recent studies reported that signaling might either antagonize or enhance c-myc activity depending on cell context. We investigated the nickel levels, demonstrated nickel, hypoxia, other mimetics degraded protein a number (A549, MCF-7, MDA-453, BT-474). The degradation c-Myc was 26S proteosome. Interestingly, knockdown both HIF-1α HIF-2α attenuated induced suggesting functional required for degradation. Further revealed two potential pathways Phosphorylation at T58 significantly increased exposed leading ubiquitination through Fbw7 ubiquitin ligase. In addition, exposure decreased USP28, de-ubiquitinating enzyme, contributing higher steady state level promoting Furthermore, reduction USP28 due transcriptional repression. levels dimethylated H3 lysine 9 promoter repressed expression. Our study phosphorylation cells, which lead enhanced proteasomal