Four-and-a-half LIM domain proteins inhibit transactivation by hypoxia-inducible factor 1.

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.
Mesh Terms:
Carcinoma, Hepatocellular, Cell Hypoxia, Feedback, Physiological, Female, Gene Expression Regulation, Neoplastic, HEK293 Cells, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Intracellular Signaling Peptides and Proteins, Kidney Neoplasms, LIM Domain Proteins, LIM-Homeodomain Proteins, Muscle Proteins, Protein Structure, Tertiary, Transcription Factors, Transcriptional Activation, Uterine Cervical Neoplasms, p300-CBP Transcription Factors
J. Biol. Chem.
Date: Feb. 24, 2012
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