Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis

Abstract

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-1 alpha. Finally, promoter activity assays showed that the VEGF promoter region containing the HIF-1alpha 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.

Missense mutation in the PTEN promoter of a patient with hemifacial hyperplasia

“…33 A novel finding was the histopathology, which also showed an unusually dense number of Schwann cells and blood vessels in the affected soft tissue biopsies and a large number of cells that were immunostained by the S100 antibody that was similar to a report by GomezManzano et al 34 The PTEN gene and promoter were sequenced because germline PTEN mutations were found in 20% of patients with Proteus and Proteus-like syndromes. 20 This study identified a novel PTEN promoter mutation in a highly conserved region positioned between two putative transcription factor binding sites.…”

PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells

“…In contrast, PTEN-induced downregulation of vascular endothelial growth factor (VEGF) results from decreased activity of the VEGF promoter (Koul et al, 2002;Gomez-Manzano et al, 2003). To determine whether PTEN regulates IGF-IR expression at the transcriptional or post-transcriptional level, we measured steady-state levels of IGF-IR mRNA in NEO-and PTEN-overexpressing clones.…”

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

“…Several studies have indicated that loss of tumor suppressors in tumors can lead to an altered phenotype in which the activities of angiogenic inducers increase relative to the activities of angiogenic inhibitors (Igarashi et al, 2002;Gomez-Manzano et al, 2003). This phenotypic change is called the angiogenic switch, a consequence of which is that transformed cells initiate the process of tumor neovascularization.…”