PMID- 9575138
OWN - NLM
STAT- MEDLINE
DCOM- 19980612
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 20
DP  - 1998 May 15
TI  - p53 inhibits hypoxia-inducible factor-stimulated transcription.
PG  - 11995-8
AB  - p53 is required for hypoxia-induced apoptosis in vivo, although the mechanism by 
      which this occurs is not known. Conversely, induction of the hypoxia-inducible 
      factor-1 (HIF-1) transactivator stimulates transcription of a number of genes 
      crucial to survival of the hypoxic state. Here we demonstrate that p53 represses 
      HIF-1-stimulated transcription. Although higher levels of p53 are required to 
      inhibit HIF than are necessary to transcriptionally activate p53 target genes, 
      these levels of p53 are similar to those that stimulate cleavage of 
      poly(ADP-ribose) polymerase, an early event in apoptosis. Transfection of 
      full-length p300 stimulates both p53-dependent and HIF-dependent transcription 
      but does not relieve p53-mediated inhibition of HIF. In contrast, a p300 
      fragment, which binds to p53 but not to HIF-1, prevents p53-dependent repression 
      of HIF activity. Transcriptionally inactive p53, mutated in its DNA binding 
      domain, retains the ability to block HIF transactivating activity, whereas a 
      transcriptionally inactive double point mutant defective for p300 binding does 
      not inhibit HIF. Finally, depletion of doxorubicin-induced endogenous p53 by E6 
      protein attenuates doxorubicin-stimulated inhibition of HIF, suggesting that a 
      p53 level sufficient for HIF inhibition can be achieved in vivo. These data 
      support a model in which stoichiometric binding of p53 to a HIF/p300 
      transcriptional complex mediates inhibition of HIF activity.
FAU - Blagosklonny, M V
AU  - Blagosklonny MV
AD  - Department of Experimental Therapeutics, NCI, National Institutes of Health, 
      Bethesda, Maryland 20892, USA. mikhailb@box-m.nih.gov
FAU - An, W G
AU  - An WG
FAU - Romanova, L Y
AU  - Romanova LY
FAU - Trepel, J
AU  - Trepel J
FAU - Fojo, T
AU  - Fojo T
FAU - Neckers, L
AU  - Neckers L
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
SB  - IM
MH  - Breast Neoplasms/metabolism/pathology
MH  - DNA-Binding Proteins/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Hydrolysis
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Nuclear Proteins/antagonists & inhibitors/*metabolism
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Promoter Regions, Genetic
MH  - *Transcription Factors
MH  - *Transcriptional Activation
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/*metabolism
EDAT- 1998/06/20 00:00
MHDA- 1998/06/20 00:01
CRDT- 1998/06/20 00:00
PHST- 1998/06/20 00:00 [pubmed]
PHST- 1998/06/20 00:01 [medline]
PHST- 1998/06/20 00:00 [entrez]
AID - S0021-9258(19)84219-9 [pii]
AID - 10.1074/jbc.273.20.11995 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 May 15;273(20):11995-8. doi: 10.1074/jbc.273.20.11995.