Cell cycle arrest and reversion of Ras-induced transformation by a conditionally activated form of mitogen-activated protein kinase kinase kinase 3

Signal-induced proliferation, differentiation, or stress responses of cells depend on mitogen-activated protein kinase (MAPK) cascades, the core modul es of which consist of members of three successively acting kinase families (MAPK kinase kinase [MAP3K], MAPK kinase, and MAPK). It is demonstrated he re that the MEKK3 kinase inhibits cell proliferation, a biologic response n ot commonly associated with members of the MAP3K family of kinases. A condi tionally activated form of MEKK3 stably expressed in fibroblasts arrests th ese cells in early G(1). MEKK3 critically blocks mitogen-driven expression of cyclin D1, a cyclin which is essential for progression of fibroblasts th rough G(1). The MEKK3-induced block of cyclin D1 expression and of cell cyc le progression may be mediated via p38 MAPK, a downstream effector of MEKK3 . The MEKK3-mediated block of proliferation also reverses Ras-induced cellu lar transformation, suggesting possible tumor-suppressing functions for thi s kinase. Together, these results suggest an involvement of the MEKK3 kinas e in negative regulation of cell cycle progression, and they provide the fi rst insights into biologic activities of this kinase.