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Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation
D Mukhopadhyay1, L Tsiokas, X M Zhou
1Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Nature
|June 15, 1995
Summary
Hypoxia induces vascular endothelial growth factor (VEGF) via a tyrosine kinase pathway. The protein tyrosine kinase c-Src is critical for this process, suggesting a role in tumor angiogenesis.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Angiogenesis is vital for tumor growth, with hypoxic tumor regions producing vascular endothelial growth factor (VEGF).
- VEGF acts as a potent angiogenic protein, driving the formation of new blood vessels.
- Understanding the signaling pathways that regulate VEGF expression under hypoxia is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the intracellular signal transduction pathway responsible for hypoxic induction of VEGF expression.
- To identify key protein kinases involved in the hypoxia-mediated VEGF signaling cascade.
- To elucidate the role of c-Src in the regulation of VEGF production during tumor development.
Main Methods:
- Utilized genistein, a protein tyrosine kinase inhibitor, to assess its effect on VEGF induction.
- Measured the kinase activity and phosphorylation status of specific tyrosine kinases, including pp60c-src, Fyn, and Yes, under hypoxic conditions.
- Employed dominant-negative mutants of c-Src and Raf-1 to determine their impact on VEGF induction.
- Analyzed VEGF induction in c-src-deficient cells to understand compensatory signaling mechanisms.
Main Results:
- Genistein effectively blocked hypoxia-induced VEGF expression, indicating the involvement of tyrosine kinases.
- Hypoxia specifically increased the kinase activity and tyrosine 416 phosphorylation of pp60c-src, without activating Fyn or Yes.
- Expression of dominant-negative c-Src or Raf-1 mutants significantly reduced VEGF induction.
- VEGF induction by hypoxia was impaired in c-src(-) cells, with a compensatory activation of Fyn observed.
Conclusions:
- The study provides insights into the intracellular signaling triggered by hypoxia, highlighting a critical role for the c-Src tyrosine kinase.
- VEGF is identified as a novel downstream target of c-Src signaling in response to hypoxia.
- These findings suggest that c-Src plays a significant role in promoting tumor angiogenesis through VEGF regulation.