IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1α activity

• Published in: Biochemical journal 2007-01, Vol.401 (1), p.341-352
• Main Authors: Huang, Jianhe, Song, Daisheng, Flores, Adrian, Zhao, Quan, Mooney, Sharon M., Shaw, Leslie M., Lee, Frank S.
• Format: Article
• Language: English
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20060635

A central means by which mammalian cells respond to low oxygen tension is through the activation of the transcription factor HIF-1 (hypoxia-inducible factor-1). Under normoxic conditions, HIF-1α (the α subunit of HIF-1) is targeted for rapid degradation by the ubiquitin–proteasome pathway. Under hypoxic conditions, this degradation is inhibited, thereby leading to the stabilization and activation of HIF-1α. Here, we report the identification of IOP1 (iron-only hydrogenase-like protein 1), a protein homologous with enzymes present in anaerobic organisms that contain a distinctive iron–sulfur cluster. IOP1 is present in a broad range of cell types. Knockdown of IOP1 using siRNA (small interfering RNA) in mammalian cells increases protein levels of HIF-1α under both normoxic and hypoxic conditions, and augments hypoxia-induced HRE (hypoxia response element) reporter gene and endogenous HIF-1α target gene expressions. We find that IOP1 knockdown up-regulates HIF-1α mRNA levels, thereby providing a mechanism by which knockdown induces the observed effects. The results collectively provide evidence that IOP1 is a component of the protein network that regulates HIF-1α in mammalian cells.