14-3-3gamma induces oncogenic transformation by stimulating MAP kinase and PI3K signaling.
The 14-3-3 proteins are a set of highly conserved scaffolding proteins that have been implicated in the regulation of a variety of important cellular processes such as the cell cycle, apoptosis and mitogenic signaling. Recent evidence indicates that the expression of some of the family members is elevated in human cancers suggesting that they may play a role in tumorigenesis. In the present study, the oncogenic potential of 14-3-3gamma was shown by focus formation and tumor formation in SCID mice using 14-3-3gamma transfected NIH3T3 mouse fibroblast cells. In contrast, 14-3-3sigma, a putative tumor suppressor, inhibited NIH3T3 transformation by H-ras and c-myc. We also report that activation of both MAP kinase and PI3K signaling pathways are essential for transformation by 14-3-3gamma. In addition, we found that 14-3-3gamma interacts with phosphatidylinositol 3-kinase (PI3K) and TSC2 proteins indicating that it could stimulate PI3K signaling by acting at two points in the signaling pathway. Overall, our studies establish 14-3-3gamma as an oncogene and implicate MAPK and PI3K signaling as important for 14-3-3gamma induced transformation.
Radhakrishnan
Vijayababu M
VM
Arizona Cancer Center, Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona, United States of America.
Martinez
Jesse D
JD
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D048948:14-3-3 Proteins; D020033:Protein Isoforms; D019869:Phosphatidylinositol 3-Kinases; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases