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Four-and-a-Half LIM Domain Proteins Inhibit Transactivation by Hypoxia-inducible Factor 1

Four-and-a-Half LIM Domain Proteins Inhibit Transactivation by Hypoxia-inducible Factor 1

Authors :
Maimon E. Hubbi
Daniele M. Gilkes
Gregg L. Semenza
Jin H. Baek
Source :
Journal of Biological Chemistry. 287:6139-6149
Publication Year :
2012
Publisher :
Elsevier BV, 2012.

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.

Details

ISSN :
00219258
Volume :
287
Database :
OpenAIRE
Journal :
Journal of Biological Chemistry
Accession number :
edsair.doi.dedup.....2e68665816fe9473d679e4cb16aecf65
Full Text :
https://doi.org/10.1074/jbc.m111.278630