PMID:16585195

Citation	Dayan, F, Roux, D, Brahimi-Horn, MC, Pouyssegur, J and Mazure, NM (2006) The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1alpha. Cancer Res. 66:3688-98
Abstract	The function of the hypoxia-inducible factor-1 (HIF-1), the key transcription factor involved in cellular adaptation to hypoxia, is restricted to low oxygen tension (pO(2)). As such, this transcription factor is central in modulating the tumor microenvironment, sensing nutrient availability, and controlling anaerobic glycolysis, intracellular pH, and cell survival. Degradation and inhibition of the limiting HIF-1alpha subunit are intimately connected in normoxia. Hydroxylation of two proline residues by prolyl hydroxylase domain (PHD) 2 protein earmarks the protein for degradation, whereas hydroxylation of an asparagine residue by factor-inhibiting HIF-1 (FIH-1 or FIH) reduces its transcriptional activity. Indeed, silencing of either PHD2 or FIH in normoxia partially induced hypoxic genes, whereas combined PHD2/FIH silencing generated a full hypoxic gene response. Given the fact that HIF-1alpha possesses two transcriptional activation domains [TAD; NH(2)-terminal (N-TAD) and COOH-terminal (C-TAD)], we hypothesized on a possible bifunctional activity of HIF-1alpha that could be discriminated by FIH, an inhibitor of the C-TAD. In human cell lines engineered to overexpress or silence FIH in response to tetracycline, we show by quantitative reverse transcription-PCR that a set of hypoxic genes (ca9, phd3, pgk1, and bnip3) respond differently toward FIH expression. This finding, extended to 26 hypoxia-induced genes, indicates differential gene expression by the N-TAD and C-TAD in response to the hypoxic gradient. We propose that the oxygen-sensitive attenuator FIH, together with two distinct TADs, is central in setting the gene expression repertoire dictated by the cell pO(2).
Links	PubMed Online version:10.1158/0008-5472.CAN-05-4564
Keywords	Adenocarcinoma/genetics; Adenocarcinoma/metabolism; Cell Line, Tumor; Colorectal Neoplasms/genetics; Colorectal Neoplasms/metabolism; Gene Expression Regulation, Neoplastic/physiology; Gene Silencing; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis; Hypoxia-Inducible Factor 1, alpha Subunit/genetics; Mixed Function Oxygenases; Procollagen-Proline Dioxygenase/antagonists & inhibitors; Procollagen-Proline Dioxygenase/genetics; Protein Structure, Tertiary; RNA, Small Interfering/genetics; Repressor Proteins/antagonists & inhibitors; Repressor Proteins/biosynthesis; Repressor Proteins/genetics; Repressor Proteins/physiology; Transcription Factors/antagonists & inhibitors; Transcription Factors/biosynthesis; Transcription Factors/genetics; Transcription Factors/physiology; Transcriptional Activation; Transfection
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HIF1N		GO:0018126: protein hydroxylation	ECO:0000314:		P		Figure 1 shows the effect of overexpression of FIH. This results in the hydroxylation of Asn.	complete

References

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