IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1alpha activity.
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-1alpha (the alpha 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-1alpha. 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-1alpha under both normoxic and hypoxic conditions, and augments hypoxia-induced HRE (hypoxia response element) reporter gene and endogenous HIF-1alpha target gene expressions. We find that IOP1 knockdown up-regulates HIF-1alpha 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-1alpha in mammalian cells.
Huang
Jianhe
J
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Song
Daisheng
D
Flores
Adrian
A
Zhao
Quan
Q
Mooney
Sharon M
SM
Shaw
Leslie M
LM
Lee
Frank S
FS
D000595:Amino Acid Sequence; D015152:Blotting, Northern; D017124:Conserved Sequence; D006801:Humans; D006864:Hydrogenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins; D007668:Kidney; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
C516542:CIAO3 protein, human; D007506:Iron-Sulfur Proteins; D010446:Peptide Fragments; D029701:Saccharomyces cerevisiae Proteins; D006864:Hydrogenase