Regulation of activating transcription factor-2 in early stage of the adipocyte differentiation program.

p38beta mitogen-activated protein kinase activity is required for the differentiation of 3T3-L1 fibroblasts into adipocytes. Activating transcription factor-2 (ATF-2) is efficiently phosphorylated and activated by p38beta kinase. These findings led us to examine a regulatory role of ATF-2 in adipocyte differentiation. The induction of ATF-2 protein precedes the expression of the transcription factors, peroxisome proliferator-activated receptor (PPAR) gamma and CCAAT/enhancer-binding protein (C/EBP) alpha. Consistent with early activation of p38beta kinase, the phosphorylation of ATF-2 was also detected in early stage of adipocyte differentiation. ATF-2 regulated gene transcription of PPARgamma, which was synergistically enhanced by p38beta kinase and C/EBPbeta proteins expression. Ectopic expression of ATF-2 in 3T3-L1 cells induced the endogenous PPARgamma protein levels. These results suggest that ATF-2 plays a role in a primary regulator of adipocyte differentiation with C/EBPbeta through promoting adipogenesis-inducing transcription factors including PPARgamma and becomes associated earlier in the differentiation program as mitotic clonal expansion proceeds and the cells become initially differentiated.