Constitutively active mitogen-activated protein kinase kinase 6 (MIKK6) orsalicylate induces spontaneous 3T3-L1 adipogenesis

Although much has been learned regarding the importance of p38 mitogen-acti vated protein kinase in inflammatory and stress responses, relatively littl e is known concerning its role in differentiation processes. Recently, we d emonstrated that p38 mitogen-activated protein kinase activity is necessary for the differentiation of 3T3-L1 fibroblasts into adipocytes (Engelman, J . A, Lisanti, M. P., and Scherer, P. E. (1998) J. Biol. Chem. 273, 32111-32 120), p38 activity is high during the initial stages of differentiation but decreases drastically as the fibroblasts undergo terminal differentiation into adipocytes. However, it remains unknown whether activation of p38 is s ufficient to stimulate adipogenesis and whether the down-regulation of p38 activity in mature adipocytes is critical for maintaining adipocyte homeost asis. In this report, we have directly addressed these questions by analyzi ng 3T3-L1 cell lines harboring a specific upstream activator of p38 (a cons titutively active mitogen-activated protein kinase kinase 6 (MKX6) mutant, MKK6(Glu)) under the control of an inducible promoter. Induction of MKK6(Gl u) in 3T3-L1 fibroblasts spurs adipocyte conversion in the absence of the h ormonal mixture normally required for efficient differentiation of wild-typ e cells. However, activation of p38 in adipocytes leads to cell death. Furt hermore, treatment of 3T3-L1 fibroblasts with salicylate, a potent stimulat or of p38, produces adipocyte-specific changes consistent with those observ ed with induction of MKK6(Glu). Expression of MKK6(Glu) in NIH-3T3 fibrobla sts (cells that do not differentiate into adipocytes under normal condition s) is capable of converting these fibroblasts into lipid-laden fat cells fo llowing hormonal stimulation. Thus, p38 activation has pro-adipogenic effec ts in multiple fibroblast cell lines.