Dual Response Mechanism of HIF1-α to Hypoxia

Abstract

Low oxygen tension, or hypoxia, triggers the expression of genes that improve oxygen delivery and glycolysis to support cell survival under this stressful state. This response requires that the transcription factor HIF1-α bind to a hypoxia-responsive element (HRE) in the promoter of target genes to increase their expression. But under normal oxygen conditions, or normoxia, HIF1-α is ubiquitinated and degraded. Hypoxia also signals growth arrest, and it is known that a stable, nondegradable, mutated form of HIF1-α can arrest the cell cycle by antagonizing the transcription factor Myc. Myc represses transcription of the cell cycle inhibitor p21 cip1 , and HIF1-α thus derepresses p21 cip1 . Koshiji et al. have determined that HIF1-α antagonizes Myc by displacing it from the p21 cip1 promoter, thus enhancing p21 cip1 expression. Neither the transcriptional activity at the C terminus of HIF1-α nor its DNA binding domain was required for this effect. Instead, the N terminus of HIF1-α was determined to functionally interact with Myc. Expression of the stable form of HIF1-α also decreased the expression of other Myc-activated genes, including BRCA1 . Neither the stable mutant nor hypoxia altered Myc expression, indicating that HIF1-α functionally antagonizes Myc. During normoxia, only Myc bound to the p21 cip1 promoter, as determined by chromatin immunoprecipitation. Hypoxia or expression of the stable form of HIF1-α caused the displacement of Myc from the p21 cip1 promoter. HIF1-α bound to the same region of the p21 cip1 promoter as did Myc, even though it appears to lack a HRE. Endogenous HIF1-α and Myc proteins were immunoprecipitated together from cells subjected to hypoxic conditions. The authors propose that although HIF1-α may directly bind to the p21 cip1 promoter, it is more likely that HIF1-α controls the Myc-regulated genes by a transient protein-protein interaction, thereby inducing cell cycle arrest. Thus, the opposite ends of the HIF1-α protein appear to regulate gene expression by distinct mechanisms. M. Koshiji, Y. Kageyama, E. A. Pete, I. Horikawa, J. C. Barrett, L. E. Huang, HIF-1α induces cell cycle arrest by functionally counteracting Myc. EMBO J . 23 , 1949-1956 (2004). [Abstract] [Full Text]