Document Detail


Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis.
MedLine Citation:
PMID:  20176937     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The HIF family of hypoxia-inducible transcription factors are key mediators of the physiologic response to hypoxia, whose dysregulation promotes tumorigenesis. One important HIF-1 effector is the REDD1 protein, which is induced by HIF-1 and which functions as an essential regulator of TOR complex 1 (TORC1) activity in Drosophila and mammalian cells. Here we demonstrate a negative feedback loop for regulation of HIF-1 by REDD1, which plays a key role in tumor suppression. Genetic loss of REDD1 dramatically increases HIF-1 levels and HIF-regulated target gene expression in vitro and confers tumorigenicity in vivo. Increased HIF-1 in REDD1(-/-) cells induces a shift to glycolytic metabolism and provides a growth advantage under hypoxic conditions, and HIF-1 knockdown abrogates this advantage and suppresses tumorigenesis. Surprisingly, however, HIF-1 up-regulation in REDD1(-/-) cells is largely independent of mTORC1 activity. Instead, loss of REDD1 induces HIF-1 stabilization and tumorigenesis through a reactive oxygen species (ROS) -dependent mechanism. REDD1(-/-) cells demonstrate a substantial elevation of mitochondrial ROS, and antioxidant treatment is sufficient to normalize HIF-1 levels and inhibit REDD1-dependent tumor formation. REDD1 likely functions as a direct regulator of mitochondrial metabolism, as endogenous REDD1 localizes to the mitochondria, and this localization is required for REDD1 to reduce ROS production. Finally, human primary breast cancers that have silenced REDD1 exhibit evidence of HIF activation. Together, these findings uncover a specific genetic mechanism for HIF induction through loss of REDD1. Furthermore, they define REDD1 as a key metabolic regulator that suppresses tumorigenesis through distinct effects on mTORC1 activity and mitochondrial function.
Authors:
Peter Horak; Andrew R Crawford; Douangsone D Vadysirisack; Zachary M Nash; M Phillip DeYoung; Dennis Sgroi; Leif W Ellisen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-02-22
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  107     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-03-10     Completed Date:  2010-05-12     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4675-80     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibiotics, Antineoplastic / pharmacology
Antioxidants / pharmacology
Ascorbic Acid / pharmacology
Blotting, Western
Cell Transformation, Viral
Cells, Cultured
Feedback, Physiological
Fibroblasts / cytology,  metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism*
Mice
Mice, Knockout
Mice, Nude
Neoplasms, Experimental / genetics,  metabolism*,  prevention & control
RNA Interference
Reactive Oxygen Species / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Sirolimus / pharmacology
Transcription Factors / genetics,  metabolism*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
J 2575-B09//Austrian Science Fund FWF; R01 CA122589/CA/NCI NIH HHS; R01CA122589/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Antioxidants; 0/Ddit4 protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Reactive Oxygen Species; 0/Transcription Factors; PQ6CK8PD0R/Ascorbic Acid; W36ZG6FT64/Sirolimus
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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