Transforming Growth Factor Beta1 Induces Hypoxia-inducible Factor-1 Stabilization Through Selective Inhibition of Phd2 Expression.
From: Immunology Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
The Journal of biological chemistry
- Publish Date: Aug 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 34
- Pages: 24171-81
- Medium: Print
- Language: English
- Citation (JAMA): McMahon Stephanie, Charbonneau Martine, Grandmont Sebastien, et al. Transforming Growth Factor Beta1 Induces Hypoxia-inducible Factor-1 Stabilization Through Selective Inhibition of Phd2 Expression.. J. Biol. Chem. Aug 2006;281:24171-81
Abstract
The hypoxia-inducible transcription factor-1 (HIF-1) is central to a number of pathological processes through the induction of specific genes such as vascular endothelial growth factor (VEGF). Even though HIF-1 is highly regulated by cellular oxygen levels, other elements of the inflammatory and tumor microenvironment were shown to influence its activity under normal oxygen concentration. Among others, recent studies indicated that transforming growth factor (TGF) beta increases the expression of the regulatory HIF-1alpha subunit, and induces HIF-1 DNA binding activity. Here, we demonstrate that TGFbeta acts on HIF-1alpha accumulation and activity by increasing HIF-1alpha protein stability. In particular, we demonstrate that TGFbeta markedly and specifically decreases both mRNA and protein levels of a HIF-1alpha-associated prolyl hydroxylase (PHD), PHD2, through the Smad signaling pathway. As a consequence, the degradation of HIF-1alpha was inhibited as determined by impaired degradation of a reporter protein containing the HIF-1alpha oxygen-dependent degradation domain encompassing the PHD-targeted prolines. Moreover, inhibition of the TGFbeta1 converting enzyme, furin, resulted in increased PHD2 expression, and decreased basal HIF-1alpha and VEGF levels, suggesting that endogenous production of bioactive TGFbeta1 efficiently regulates HIF-1-targeted genes. This was reinforced by results from HIF-1alpha knock-out or HIF-1alpha-inhibited cells that show impairment in VEGF production in response to TGFbeta. This study reveals a novel mechanism by which a growth factor controls HIF-1 stability, and thereby drives the expression of specific genes, through the regulation of PHD2 levels.
Mesh Headings (Keywords): Animals, Cell Line, Tumor, Furin, Gene Expression Regulation, Humans, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation, Mice, Procollagen-Proline Dioxygenase, Recombinant Proteins, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Transforming Growth Factor beta1, Vascular Endothelial Growth Factor A
Check for Full Text / PubMed Unique Identifier (PMID): 16815840
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.