Role of the beta isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation.
The 14-3-3 proteins are associated with proto-oncogene and oncogene products. Here, we generated NIH 3T3 cells overexpressing the beta isoform of the 14-3-3 proteins (14-3-3 beta) to examine the function of this isoform in cellular proliferation and oncogenic transformation. Overexpression of 14-3-3 beta in NIH 3T3 cells stimulated cell growth and supported anchorage-independent growth in soft agar medium and tumor formation in nude mice. To elucidate the molecular mechanisms of 14-3-3 beta-mediated NIH 3T3 transformation, we examined the activity of mitogen-activated protein kinase (MAPK) after serum stimulation. Overexpression of 14-3-3 beta augmented MAPK activity after serum stimulation, and MAPK activity correlated well with the amount of 14-3-3 beta expression. The colony-forming ability of NIH 3T3 cells overexpressing 14-3-3 beta in soft agar medium was efficiently abolished by exogenous expression of a dominant-negative mutant of MEK1 and 14-3-3 beta physically interacted with Raf-1 in these cells. These findings indicate that 14-3-3 beta has oncogenic potential, mainly through enhancement of Raf-1 activation and resultant augmentation of signaling in the MAPK cascade.
Takihara
Y
Y
Department of Medical Genetics and Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan. takihara@biken.osaka-u.ac.jp
Matsuda
Y
Y
Hara
J
J
D048948:14-3-3 Proteins; D016475:3T3 Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D048948:14-3-3 Proteins; D020033:Protein Isoforms; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases