Abstract
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that promotes angiogenesis, metabolic reprogramming, and other critical aspects of cancer biology. The four-and-a-half LIM domain (FHL) proteins are a family of LIM domain-only proteins implicated in transcriptional regulation and suppression of tumor growth. Here we describe functional interactions between the FHL proteins and HIF-1. FHL1-3 inhibit HIF-1 transcriptional activity and HIF-1α transactivation domain function by oxygen-independent mechanisms. FHL2 directly interacts with HIF-1α to repress transcriptional activity. FHL1 binds to the p300/CBP co-activators and disrupts binding with HIF-1α. FHL3 does not bind to HIF-1α or p300, indicating that it regulates transactivation by a novel molecular mechanism. Expression of the FHL proteins increased upon HIF-1α induction, suggesting the existence of a feedback loop. These results identify FHL proteins as negative regulators of HIF-1 activity, which may provide a mechanism by which they suppress tumor growth.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Cell Hypoxia / physiology
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Feedback, Physiological / physiology
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Female
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Gene Expression Regulation, Neoplastic / physiology
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HEK293 Cells
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HeLa Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism*
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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LIM Domain Proteins / chemistry
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LIM Domain Proteins / metabolism*
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LIM-Homeodomain Proteins / chemistry
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LIM-Homeodomain Proteins / metabolism*
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Muscle Proteins / chemistry
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Muscle Proteins / metabolism*
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Protein Structure, Tertiary / physiology
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Transcription Factors / chemistry
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Transcription Factors / metabolism*
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Transcriptional Activation / physiology*
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
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p300-CBP Transcription Factors / metabolism
Substances
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FHL1 protein, human
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FHL2 protein, human
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FHL3 protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intracellular Signaling Peptides and Proteins
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LIM Domain Proteins
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LIM-Homeodomain Proteins
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Muscle Proteins
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Transcription Factors
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p300-CBP Transcription Factors