期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 9, 页码 6139-6149出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.278630
关键词
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资金
- National Institutes of Health Public Health Service [N01-HV28180, HHS-N268201000032C]
- Johns Hopkins Institute for Cell Engineering
- National Institutes of Health [T32-HL007525-27]
- Cellular and Molecular Medicine Predoctoral Training Grant [T32-GM008752-11]
- Komen Postdoctoral Fellowship
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-1 alpha transactivation domain function by oxygen-independent mechanisms. FHL2 directly interacts with HIF-1 alpha to repress transcriptional activity. FHL1 binds to the p300/CBP co-activators and disrupts binding with HIF-1 alpha. FHL3 does not bind to HIF-1 alpha or p300, indicating that it regulates transactivation by a novel molecular mechanism. Expression of the FHL proteins increased upon HIF-1 alpha 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.
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