MAP kinase activation is essential for oncogenic transformation of NIH3T3 cells by Mos.
The c-mos proto-oncogene product, Mos, is a serine/threonine protein kinase that controls the meiotic cell cycle in vertebrate oocytes. Both in vivo and in vitro, Mos can activate mitogen-activated protein kinase (MAPK) most probably by direct phosphorylation of MAPK kinase (MAPKK). In many cell types transformed by diverse oncogene products such as Raf, MAPK is constitutively activated, suggesting that the MAPK pathway may mediate oncogenic signalling by many oncogene products. Using mouse NIH3T3 cells, we examined whether oncogenic transformation by Mos is mediated by MAPK activation. Coexpression of a kinase-defective (dominant-negative) mutant of Mek1, one of the MAPKK isoforms, completely suppressed transformation by Mos. By contrast, coexpression of wild-type Mek1 markedly enhanced the transforming efficiency of Mos. Moreover, overexpression of the dominant-negative Mek1 reverted the transformation phenotype of Mos-transformed cells. These results indicate that in NIH3T3 cells the Mek1/MAPK pathway is necessary and sufficient for transformation (and its maintenance) by Mos. Transformation of NIH3T3 cells by Raf or Ras was also suppressed by the dominant-negative Mek1, but significantly less efficiently than that by Mos, suggesting the existence of multiple signalling pathways for Raf and Ras oncoproteins.
Okazaki
K
K
Division of Molecular Genetics, Kurume University, Fukuoka, Japan.
Sagata
N
N
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017231:Proto-Oncogene Proteins c-mos / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins / Q000378:metabolism
D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017231:Proto-Oncogene Proteins c-mos; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins