PMID- 15199132
OWN - NLM
STAT- MEDLINE
DCOM- 20040804
LR  - 20181113
IS  - 0270-7306 (Print)
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Linking)
VI  - 24
IP  - 13
DP  - 2004 Jul
TI  - DNA damage is a prerequisite for p53-mediated proteasomal degradation of 
      HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic 
      anhydrase IX.
PG  - 5757-66
AB  - We investigated the relationship between the tumor suppressor p53 and the 
      hypoxia-inducible factor-1 (HIF-1)-dependent expression of the hypoxia marker, 
      carbonic anhydrase IX (CAIX). MCF-7 (wt p53) and Saos-2 (p53-null) cells 
      displayed similar induction of CAIX expression and CA9 promoter activity under 
      hypoxic conditions. Activation of p53 by the DNA damaging agent mitomycin C (MC) 
      was accompanied by a potent repression of CAIX expression and the CA9 promoter in 
      MCF-7 but not in Saos-2 cells. The activated p53 mediated increased proteasomal 
      degradation of HIF-1alpha protein, resulting in considerably lower steady-state 
      levels of HIF-1alpha protein in hypoxic MCF-7 cells but not in Saos-2 cells. 
      Overexpression of HIF-1alpha relieved the MC-induced repression in MCF-7 cells, 
      confirming regulation at the HIF-1alpha level. Similarly, CA9 promoter activity 
      was downregulated by MC in HCT 116 p53(+/+) but not the isogenic p53(-/-) cells. 
      Activated p53 decreased HIF-1alpha protein levels by accelerated 
      proteasome-dependent degradation without affecting significantly HIF-1alpha 
      transcription. In summary, our results demonstrate that the presence of wtp53 
      under hypoxic conditions has an insignificant effect on the stabilization of 
      HIF-1alpha protein and HIF-1-dependent expression of CAIX. However, upon 
      activation by DNA damage, wt p53 mediates an accelerated degradation of 
      HIF-1alpha protein, resulting in reduced activation of CA9 transcription and, 
      correspondingly, decreased levels of CAIX protein. A model outlining the 
      quantitative relationship between p53, HIF-1alpha, and CAIX is presented.
FAU - Kaluzova, Milota
AU  - Kaluzova M
AD  - Department of Microbiology and Molecular Genetics, University of California at 
      Irvine, College of Medicine, Irvine 92717, USA.
FAU - Kaluz, Stefan
AU  - Kaluz S
FAU - Lerman, Michael I
AU  - Lerman MI
FAU - Stanbridge, Eric J
AU  - Stanbridge EJ
LA  - eng
GR  - N01-CO-56000/CO/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 50SG953SK6 (Mitomycin)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 4.2.1.1 (CA9 protein, human)
RN  - EC 4.2.1.1 (Carbonic Anhydrase IX)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
SB  - IM
MH  - Antigens, Neoplasm/genetics/*metabolism
MH  - Carbonic Anhydrase IX
MH  - Carbonic Anhydrases/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - Cysteine Endopeptidases/*metabolism
MH  - *DNA Damage
MH  - Down-Regulation/drug effects
MH  - Humans
MH  - Hypoxia/enzymology/*metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Mitomycin/pharmacology
MH  - Promoter Regions, Genetic
MH  - Transcription Factors/biosynthesis/*metabolism
MH  - Transcription, Genetic
MH  - Tumor Suppressor Protein p53/deficiency/genetics/*physiology
PMC - PMC480909
EDAT- 2004/06/17 05:00
MHDA- 2004/08/05 05:00
PMCR- 2004/07/01
CRDT- 2004/06/17 05:00
PHST- 2004/06/17 05:00 [pubmed]
PHST- 2004/08/05 05:00 [medline]
PHST- 2004/06/17 05:00 [entrez]
PHST- 2004/07/01 00:00 [pmc-release]
AID - 24/13/5757 [pii]
AID - 1958-03 [pii]
AID - 10.1128/MCB.24.13.5757-5766.2004 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2004 Jul;24(13):5757-66. doi: 10.1128/MCB.24.13.5757-5766.2004.