PMID- 16543245
OWN - NLM
STAT- MEDLINE
DCOM- 20060721
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 281
IP  - 20
DP  - 2006 May 19
TI  - Hypoxic regulation of vascular endothelial growth factor through the induction of 
      phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc.
PG  - 13957-63
AB  - The induction of vascular endothelial growth factor (VEGF) is an essential 
      feature of tumor angiogenesis. Hypoxia is a potent stimulator of VEGF expression, 
      and hypoxia-inducible factor-1 (HIF-1) is considered to be critical for this 
      induction. However, we have previously demonstrated that induction of VEGF by 
      hypoxia was preserved when HIF-1alpha was silenced. We sought to better define 
      the molecular basis of this HIF-1-independent regulation. In colon cancer cells, 
      hypoxia stimulated multiple K-ras effector pathways including 
      phosphatidylinositol 3-kinase. VEGF promoter deletion studies identified a novel 
      promoter region between -418 and -223 bp that was responsive to hypoxia in a 
      PI3K/Rho/ROCK-dependent manner. Electrophoretic mobility shift assays identified 
      a fragment between -300 and -251 bp that demonstrated a unique shift only in 
      hypoxic conditions. Inhibition of PI3K or ROCK blocked the formation of this 
      complex. A binding site for c-Myc, a target of ROCK, was identified at -271 bp. A 
      role for c-Myc in the hypoxic induction of VEGF was demonstrated by site-directed 
      mutagenesis of the VEGF promoter and silencing of c-Myc by small interfering RNA. 
      Collectively, these findings suggest an alternative mechanism for the hypoxic 
      induction of VEGF in colon cancer that does not depend upon HIF-1alpha but 
      instead requires the activation of PI3K/Rho/ROCK and c-Myc.
FAU - Mizukami, Yusuke
AU  - Mizukami Y
AD  - Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and 
      Harvard Medical School, Boston, Massachusetts 02114, USA.
FAU - Fujiki, Kotoyo
AU  - Fujiki K
FAU - Duerr, Eva-Maria
AU  - Duerr EM
FAU - Gala, Manish
AU  - Gala M
FAU - Jo, Won-Seok
AU  - Jo WS
FAU - Zhang, Xiaobo
AU  - Zhang X
FAU - Chung, Daniel C
AU  - Chung DC
LA  - eng
GR  - CA92594/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 - 20060316
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (rho-Associated Kinases)
SB  - IM
MH  - Base Sequence
MH  - Colonic Neoplasms/metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - *Hypoxia
MH  - Intracellular Signaling Peptides and Proteins
MH  - Models, Biological
MH  - Molecular Sequence Data
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-myc/*metabolism
MH  - Vascular Endothelial Growth Factor A/genetics/*metabolism
MH  - rho-Associated Kinases
EDAT- 2006/03/18 09:00
MHDA- 2006/07/22 09:00
CRDT- 2006/03/18 09:00
PHST- 2006/03/18 09:00 [pubmed]
PHST- 2006/07/22 09:00 [medline]
PHST- 2006/03/18 09:00 [entrez]
AID - S0021-9258(20)78037-3 [pii]
AID - 10.1074/jbc.M511763200 [doi]
PST - ppublish
SO  - J Biol Chem. 2006 May 19;281(20):13957-63. doi: 10.1074/jbc.M511763200. Epub 2006 
      Mar 16.