Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1.
The cellular response to hypoxia is, at least in part, mediated by the transcriptional regulation of hypoxia-responsive genes involved in balancing the intracellular ATP production and consumption. Recent evidence suggests that the transcription factor, HIF-1alpha, functions as a master regulator of oxygen homeostasis by controlling a broad range of cellular events in hypoxia. In normoxia, HIF-1alpha is targeted for destruction via prolyl hydroxylation, an oxygen-dependent modification that signals for recognition by the ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor. Three HIF prolyl hydroxylases (EGLN1, EGLN2, and EGLN3) have been identified in mammals, among which EGLN1 and EGLN3 are hypoxia-inducible at their mRNA levels in an HIF-1alpha-dependent manner. In this study, we demonstrated that apart from promoting HIF-1alpha proteolysis in normoxia, EGLN1 specifically represses HIF-1alpha transcriptional activity in hypoxia. Ectopic expression of EGLN1 inhibited HIF-1alpha transcriptional activity without altering its protein levels in a von Hippel-Lindau-deficient cell line, indicating a discrete activity of EGLN1 in transcriptional repression. Conversely, silencing of EGLN1 expression augmented HIF-1alpha transcriptional activity and its target gene expression in hypoxia. Thus, we proposed that the accumulated EGLN1 in hypoxia acts as a negative-feedback mechanism to modulate HIF-1alpha target gene expression. Our finding also provided new insight into the pharmacological manipulation of the HIF prolyl hydroxylase for ischemic diseases.
To
Kenneth K W
KK
Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
Huang
L Eric
LE
D000818:Animals; D002460:Cell Line; D020868:Gene Silencing; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D014158:Transcription, Genetic
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017874:Immediate-Early Proteins; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen