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 lines and that the extracellular signal-regulated kinase (ERK) and p38 kinase differentially regulate the oncogene-mediated stimulation of VEGF. The highest 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 PD98059 MEK inhibitor was used to block the ERK pathway and SB203580 inhibitor to block the p38 pathway. The parent and the v-H-ras transformed RLE cell lines 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 comparable manner in a human breast carcinoma cell line. In the v-raf and v-myc transformed RLE lines, positive regulation of VEGF was transduced through the p38 pathway. These findings suggest that (1) oncogenic ras differs from raf and myc in the recruitment of the MAPK signaling pathways for VEGF regulation; (2) that VEGF is regulated in ras transformed and human cancer cell lines in a positive and negative manner by the ERK and p38 signaling pathways.
Okajima
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Tumor Biology and Carcinogenesis Section, Laboratory of Cellular Carcinogenesis and Tumor Promotion, Bethesda, Maryland 20892, USA.
Thorgeirsson
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UP
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D016259:Genes, myc; D011905:Genes, ras; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics; D027384:Oncogene Proteins v-raf; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases
D016228:Endothelial Growth Factors; D005419:Flavonoids; D007093:Imidazoles; D008222:Lymphokines; D011725:Pyridines; D015682:Retroviridae Proteins, Oncogenic; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D027384:Oncogene Proteins v-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one