PMID- 16585195
OWN - NLM
STAT- MEDLINE
DCOM- 20060522
LR  - 20131121
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 7
DP  - 2006 Apr 1
TI  - The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls 
      expression of distinct genes through the bifunctional transcriptional character 
      of hypoxia-inducible factor-1alpha.
PG  - 3688-98
AB  - 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).
FAU - Dayan, Frederic
AU  - Dayan F
AD  - Institute of Signaling, Developmental Biology and Cancer Research, Centre 
      National de la Recherche Scientifique, UMR 6543, Universite de Nice, Centre 
      Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice, France.
FAU - Roux, Daniele
AU  - Roux D
FAU - Brahimi-Horn, M Christiane
AU  - Brahimi-Horn MC
FAU - Pouyssegur, Jacques
AU  - Pouyssegur J
FAU - Mazure, Nathalie M
AU  - Mazure NM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.11.- (HIF1AN protein, human)
RN  - EC 1.14.11.2 (EGLN1 protein, human)
RN  - EC 1.14.11.2 (Procollagen-Proline Dioxygenase)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
SB  - IM
MH  - Adenocarcinoma/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Colorectal Neoplasms/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic/*physiology
MH  - Gene Silencing
MH  - HeLa Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis/*genetics
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases
MH  - Mixed Function Oxygenases
MH  - Procollagen-Proline Dioxygenase/antagonists & inhibitors/genetics
MH  - Protein Structure, Tertiary
MH  - RNA, Small Interfering/genetics
MH  - Repressor Proteins/antagonists & inhibitors/biosynthesis/genetics/*physiology
MH  - Transcription Factors/antagonists & inhibitors/biosynthesis/genetics/*physiology
MH  - Transcriptional Activation
MH  - Transfection
EDAT- 2006/04/06 09:00
MHDA- 2006/05/23 09:00
CRDT- 2006/04/06 09:00
PHST- 2006/04/06 09:00 [pubmed]
PHST- 2006/05/23 09:00 [medline]
PHST- 2006/04/06 09:00 [entrez]
AID - 66/7/3688 [pii]
AID - 10.1158/0008-5472.CAN-05-4564 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Apr 1;66(7):3688-98. doi: 10.1158/0008-5472.CAN-05-4564.