PMID- 12186875
OWN - NLM
STAT- MEDLINE
DCOM- 20021219
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 277
IP  - 42
DP  - 2002 Oct 18
TI  - Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible 
      factor-1alpha.
PG  - 40112-7
AB  - Stabilization of the hypoxia-inducible factor-1 (HIF-1) protein is essential for 
      its role as a regulator of gene expression under low oxygen conditions. Here, 
      employing a novel hydroxylation-specific antibody, we directly show that proline 
      564 of HIF-1alpha and proline 531 of HIF-2alpha are hydroxylated under normoxia. 
      Importantly, HIF-1alpha Pro-564 and HIF-2alpha Pro-531 hydroxylation is 
      diminished with the treatment of hypoxia, cobalt chloride, desferrioxamine, or 
      dimethyloxalyglycine, regardless of the E3 ubiquitin ligase activity of the von 
      Hippel-Lindau (VHL) tumor suppressor gene. Furthermore, in VHL-deficient cells, 
      HIF-1alpha Pro-564 and HIF-2alpha Pro-531 had detectable amounts of hydroxylation 
      following transition to hypoxia, indicating that the post-translational 
      modification is not reversible. The introduction of v-Src or RasV12 oncogenes 
      resulted in the stabilization of normoxic HIF-1alpha and the loss of hydroxylated 
      Pro-564, demonstrating that oncogene-induced stabilization of HIF-1alpha is 
      signaled through the inhibition of prolyl hydroxylation. Conversely, a 
      constitutively active Akt oncogene stabilized HIF-1alpha under normoxia 
      independently of prolyl hydroxylation, suggesting an alternative mechanism for 
      HIF-1alpha stabilization. Thus, these results indicate distinct pathways for 
      HIF-1alpha stabilization by different oncogenes. More importantly, these findings 
      link oncogenesis with normoxic HIF-1alpha expression through prolyl 
      hydroxylation.
FAU - Chan, Denise A
AU  - Chan DA
AD  - Program in Cancer Biology, Department of Radiation Oncology, Stanford University, 
      Stanford, California 94305, USA.
FAU - Sutphin, Patrick D
AU  - Sutphin PD
FAU - Denko, Nicholas C
AU  - Denko NC
FAU - Giaccia, Amato J
AU  - Giaccia AJ
LA  - eng
GR  - CA09302/CA/NCI NIH HHS/United States
GR  - CA67166/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20020816
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Amino Acids, Dicarboxylic)
RN  - 0 (Chelating Agents)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Transcription Factors)
RN  - 3G0H8C9362 (Cobalt)
RN  - 9DLQ4CIU6V (Proline)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.13.12.- (Luciferases)
RN  - EVS87XF13W (cobaltous chloride)
RN  - J06Y7MXW4D (Deferoxamine)
RN  - VVW38EB8YS (oxalylglycine)
SB  - IM
MH  - Amino Acids, Dicarboxylic/pharmacology
MH  - Animals
MH  - Chelating Agents/pharmacology
MH  - Cobalt/pharmacology
MH  - Deferoxamine/pharmacology
MH  - Fibroblasts/metabolism
MH  - Hydroxylation
MH  - Hypoxia
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunoblotting
MH  - Iron/metabolism
MH  - Luciferases/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Proline/*chemistry/metabolism
MH  - Protein Binding
MH  - Transcription Factors/*metabolism
MH  - Transfection
EDAT- 2002/08/21 10:00
MHDA- 2002/12/20 04:00
CRDT- 2002/08/21 10:00
PHST- 2002/08/21 10:00 [pubmed]
PHST- 2002/12/20 04:00 [medline]
PHST- 2002/08/21 10:00 [entrez]
AID - S0021-9258(19)72386-2 [pii]
AID - 10.1074/jbc.M206922200 [doi]
PST - ppublish
SO  - J Biol Chem. 2002 Oct 18;277(42):40112-7. doi: 10.1074/jbc.M206922200. Epub 2002 
      Aug 16.