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Vol. 10, Issue 4, 907-919, April 1999
*Hanson Centre for Cancer Research, Adelaide, South Australia 5000, Australia; and Vascular endothelial growth factor (VEGF) is a key regulator of
developmental, physiological, and tumor angiogenesis. Upregulation of
VEGF expression by hypoxia appears to be a critical step in the
neovascularization of solid cancers. The VEGF mRNA is intrinsically labile, but in response to hypoxia the mRNA is stabilized. We have
systematically analyzed the regions in the VEGF mRNA that are
responsible for its lability under normoxic conditions and for
stabilization in response to hypoxia. We find that the VEGF mRNA not
only contains destabilizing elements in its 3' untranslated region
(3'UTR), but also contains destabilizing elements in the 5'UTR and
coding region. Each region can independently promote mRNA degradation,
and together they act additively to effect rapid degradation under
normoxic conditions. Stabilization of the mRNA in response to hypoxia
is completely dependent on the cooperation of elements in each of the
5'UTR, coding region, and 3'UTR. Combinations of any of two of these
three regions were completely ineffective in responding to hypoxia,
whereas combining all three regions allowed recapitulation of the
hypoxic stabilization seen with the endogenous VEGF mRNA. We conclude
that multiple regions in the VEGF mRNA cooperate both to ensure the
rapid degradation of the mRNA under normoxic conditions and to allow
stabilization of the mRNA in response to hypoxia. Our findings
highlight the complexity of VEGF gene expression and also reveal a
mechanism of gene regulation that could become the target for
strategies of therapeutic intervention.
Max-Planck-Institut für
physiologische und klinische Forshung, W. G. Kerckhoff Institut,
Abteilung Molekulare Zellbiologie, 61231 Bad Nauheim, Germany
Corresponding author. E-mail address:
greg.GOODALL{at}imvs.sa.gov.au.
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