Different regulation of vascular endothelial growth factor expression by the ERK and p38 kinase pathways in v-ras, v-raf, and v-myc transformed cells

Here we show that vascular endothelial growth factor (VEGF) mRNA expression is up-regulated in oncogene transformed rat liver epithelial (RLE) cell li nes and that the extracellular signal-regulated kinase (ERK) and p38 kinase differentially regulate the oncogene-mediated stimulation of VEGF. The hig hest level of VEGF mRNA expression was observed in the v-H-ras transformed RLE cell line, followed by the v-raf and v-myc transformed lines. The PD980 59 MEK inhibitor was used to block the ERK pathway and SB203580 inhibitor t o block the p38 pathway. The parent and the v-H-ras transformed RLE cell li nes showed up-regulation of VEGF RNA expression through the ERK pathway and down-regulation of VEGF through the p38 pathway. VEGF was regulated in a c omparable manner in a human breast carcinoma cell line. In the v-raf and v- myc transformed RLE Lines, positive regulation of VEGF was transduced throu gh the p38 pathway. These findings suggest that (1) oncogenic ms differs fr om raf and myc in the recruitment of the MAPK signaling pathways for VEGF r egulation; (2) that VEGF is regulated in ras transformed and human cancer c ell Lines in a positive and negative manner by the ERK and p38 signaling pa thways. (C) 2000 Academic Press.