Abstract
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 14-3-3γ was shown by focus formation and tumor formation in SCID mice using 14-3-3γ transfected NIH3T3 mouse fibroblast cells. In contrast, 14-3-3σ, 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 14-3-3γ. In addition, we found that 14-3-3γ 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 14-3-3γ as an oncogene and implicate MAPK and PI3K signaling as important for 14-3-3γ induced transformation.
Highlights
14-3-3 proteins are a family of highly conserved proteins that interact with and regulate a diverse array of cellular proteins
There is mounting evidence that 14-3-3 proteins play a role in the development of human tumors [7]. This notion is most compellingly supported by studies which show that the expression of one family member, 14-3-3s, is down regulated in breast cancers [8] and it acts as a tumor suppressor [9]
Using focus formation assays, we show that 143-3c is an oncogene and that it functions by activating the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. 14-3-3s, in contrast, suppresses focus formation and inhibits activation of both of these signaling pathways
Summary
14-3-3 proteins are a family of highly conserved proteins that interact with and regulate a diverse array of cellular proteins. There is mounting evidence that 14-3-3 proteins play a role in the development of human tumors [7] This notion is most compellingly supported by studies which show that the expression of one family member, 14-3-3s, is down regulated in breast cancers [8] and it acts as a tumor suppressor [9]. We and others have shown that 14-3-3 expression is aberrantly up regulated in several tumor types including lung cancer [11,12,13] This suggests that abnormal expression of these proteins have a role in cancer; the mechanism by which these proteins promote neoplastic progression is not well understood. Using focus formation assays, we show that 143-3c is an oncogene and that it functions by activating the MAPK and PI3K pathways. 14-3-3s, in contrast, suppresses focus formation and inhibits activation of both of these signaling pathways
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