PMID- 19880525
OWN - NLM
STAT- MEDLINE
DCOM- 20100222
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 285
IP  - 4
DP  - 2010 Jan 22
TI  - Complex regulation of the transactivation function of hypoxia-inducible factor-1 
      alpha by direct interaction with two distinct domains of the CREB-binding 
      protein/p300.
PG  - 2601-9
LID - 10.1074/jbc.M109.021824 [doi]
AB  - Activation of transcription in response to low oxygen tension is mediated by the 
      hypoxia-inducible factor-1 (HIF-1). HIF-1 is a heterodimer of two proteins: aryl 
      hydrocarbon receptor nuclear translocator and the oxygen-regulated HIF-1 alpha. 
      The C-terminal activation domain of HIF-1 alpha has been shown to interact with 
      cysteine/histidine-rich region 1 (CH1) of the coactivator CBP/p300 in a 
      hypoxia-dependent manner. However, HIF forms lacking C-terminal activation domain 
      (naturally occurring or genetically engineered) are still able to activate 
      transcription of target genes in hypoxia. Here, we demonstrate that the 
      N-terminal activation domain (N-TAD) of HIF-1 alpha interacts with endogenous CBP 
      and that this interaction facilitates its transactivation function. Our results 
      show that interaction of HIF-1 alpha N-TAD with CBP/p300 is mediated by the CH3 
      region of CBP known to interact with, among other factors, p53. Using 
      fluorescence resonance energy transfer experiments, we demonstrate that N-TAD 
      interacts with CH3 in vivo. Coimmunoprecipitation assays using endogenous 
      proteins showed that immunoprecipitation of CBP in hypoxia results in the 
      recovery of a larger fraction of HIF-1 alpha than of p53. Chromatin 
      immunoprecipitation demonstrated that at 1% O(2) CBP is recruited to a HIF-1 
      alpha but not to a p53 target gene. Upon activation of both pathways, lower 
      levels of chromatin-associated CBP were detected at either target gene promoter. 
      These results identify CBP as the coactivator directly interacting with HIF-1 
      alpha N-TAD and mediating the transactivation function of this domain. Thus, we 
      suggest that in hypoxia HIF-1 alpha is a major CBP-interacting transcription 
      factor that may compete with other CBP-dependent factors, including p53, for 
      limiting amounts of this coactivator, underscoring the complexity in the 
      regulation of gene expression by HIF-1 alpha.
FAU - Ruas, Jorge L
AU  - Ruas JL
AD  - Department of Cell and Molecular Biology, Karolinska Institutet, von Eulers vag 
      3, S-171 77 Stockholm, Sweden.
FAU - Berchner-Pfannschmidt, Utta
AU  - Berchner-Pfannschmidt U
FAU - Malik, Sohail
AU  - Malik S
FAU - Gradin, Katarina
AU  - Gradin K
FAU - Fandrey, Joachim
AU  - Fandrey J
FAU - Roeder, Robert G
AU  - Roeder RG
FAU - Pereira, Teresa
AU  - Pereira T
FAU - Poellinger, Lorenz
AU  - Poellinger L
LA  - eng
GR  - DK071900/DK/NIDDK NIH HHS/United States
GR  - DK060764/DK/NIDDK NIH HHS/United States
GR  - R01 DK060764/DK/NIDDK NIH HHS/United States
GR  - R01 DK071900/DK/NIDDK NIH HHS/United States
GR  - R01 CA129325/CA/NCI NIH HHS/United States
GR  - CA129325/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091030
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Chelating Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 4QD397987E (Histidine)
RN  - 551W113ZEP (2,2'-Dipyridyl)
RN  - EC 2.3.1.48 (E1A-Associated p300 Protein)
RN  - EC 2.3.1.48 (p300-CBP Transcription Factors)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - 2,2'-Dipyridyl/pharmacology
MH  - Cell Line
MH  - Chelating Agents/pharmacology
MH  - Cysteine/metabolism
MH  - E1A-Associated p300 Protein/chemistry/*metabolism
MH  - HeLa Cells
MH  - Histidine/metabolism
MH  - Humans
MH  - Hypoxia/metabolism/*physiopathology
MH  - *Hypoxia-Inducible Factor 1, alpha Subunit/chemistry/genetics/metabolism
MH  - Kidney/cytology
MH  - Mutagenesis
MH  - Protein Interaction Domains and Motifs/drug effects/physiology
MH  - Protein Structure, Tertiary
MH  - Transcriptional Activation/physiology
MH  - Tumor Suppressor Protein p53/metabolism
MH  - p300-CBP Transcription Factors/chemistry/*metabolism
PMC - PMC2807317
EDAT- 2009/11/03 06:00
MHDA- 2010/02/23 06:00
PMCR- 2011/01/22
CRDT- 2009/11/03 06:00
PHST- 2009/11/03 06:00 [entrez]
PHST- 2009/11/03 06:00 [pubmed]
PHST- 2010/02/23 06:00 [medline]
PHST- 2011/01/22 00:00 [pmc-release]
AID - S0021-9258(19)63754-3 [pii]
AID - M109.021824 [pii]
AID - 10.1074/jbc.M109.021824 [doi]
PST - ppublish
SO  - J Biol Chem. 2010 Jan 22;285(4):2601-9. doi: 10.1074/jbc.M109.021824. Epub 2009 
      Oct 30.