Activated Neu/ErbB-2 induces expression of the vascular endothelial growth factor gene by functional activation of...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• The neu (c-erbB-2 or HER2) proto-oncogene encodes a receptor tyrosine kinase overexpressed in breast and ovarian cancers.
• Oncogenic activation of Neu can occur through various molecular mechanisms, contributing to tumor development and progression.
• Tumor angiogenesis, driven by factors like VEGF, is crucial for cancer growth and metastasis.

Purpose of the Study:

• To investigate the effect of activated Neu receptor signaling on the expression of the tumor angiogenesis factor VEGF.
• To elucidate the molecular mechanisms by which Neu influences VEGF expression.
• To determine the role of transcription factors in mediating Neu-induced VEGF production.

Main Methods:

• Utilized Rat-1 cells expressing wild-type and activated Neu receptors.
• Assessed VEGF expression at both mRNA and protein levels.
• Investigated the transcriptional activation of the VEGF promoter using Sp1 binding sites.
• Employed GAL4-based transactivation assays to analyze Sp1 activity.

Main Results:

• Expression of activated Neu receptors, but not wild-type Neu, significantly increased VEGF expression at mRNA and protein levels.
• Neu-induced VEGF expression was mediated by the transcriptional activation of the VEGF promoter through Sp1 binding sites.
• Neu transformation did not alter Sp1 expression or its promoter binding activity.
• Functional changes in Sp1, leading to transactivation, were observed in Neu-transformed cells.

Conclusions:

• Activated Neu receptor signaling triggers a cascade that leads to increased VEGF expression.
• The transcription factor Sp1 plays a critical role in mediating Neu-induced VEGF promoter activation.
• Understanding this signaling pathway provides insights into targeting tumor angiogenesis in Neu-overexpressing cancers.