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Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis
Author(s) -
GomezManzano Candelaria,
Fueyo Juan,
Jiang Hong,
Glass Tricia L.,
Lee HoYoung,
Hu Min,
Liu JuinnLin,
Jasti Sushma L.,
Liu TaJen,
Conrad Charles A.,
Yung W. K. Alfred
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10396
Subject(s) - pten , downregulation and upregulation , cancer research , angiogenesis , vascular endothelial growth factor , protein kinase b , glioma , signal transduction , biology , western blot , tumor suppressor gene , pi3k/akt/mtor pathway , chemistry , microbiology and biotechnology , cancer , carcinogenesis , gene , vegf receptors , biochemistry , genetics
Inactivation of the tumor suppressor gene PTEN and overexpression of VEGF are two of the most common events observed in high‐grade malignant gliomas. The purpose of this study was to determine whether PTEN controls VEGF expression in gliomas under normoxic conditions. Transfer of PTEN to human glioma cells resulted in the transduction of a functional PTEN protein as evidenced by the upregulation of p27 and modification of the phosphorylation status of Akt. Under normoxic conditions, enzyme‐linked immunosorbent assay and Northern blot analyses showed downregulation of VEGF in PTEN‐treated cells. Moreover, conditioned media from PTEN‐treated glioma cells significantly diminished the ability of endothelial cells to grow and migrate. Western blot assays demonstrated that, in a normoxic environment, PTEN downregulates HIF‐1α. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF‐1α binding site is necessary and sufficient for PTEN‐mediated downregulation of VEGF. Experiments with PI3‐K inhibitors and kinase assays suggested that PI3‐K is mediating the effect of PTEN on VEGF, and not the p42/p48 or p38 MAP kinases. These results indicate that restoration of PTEN function in gliomas may induce therapeutic effect by downregulating VEGF. Furthermore, this close functional relationship between PTEN and VEGF suggests that a better understanding of the transduction signal regulated by PTEN might enhance the knowledge of the cause and physiology of vascular and inflammatory diseases. Ann Neurol 2003