Inhibition of the terminal stages of adipocyte differentiation by cMyc

The nuclear oncoprotein Myc is a pivotal regulator of several important bio logical processes, including cellular proliferation, differentiation, and a poptosis, Deregulated Myc expression is incompatible with terminal differen tiation in a variety of cell types, including adipocytes, To understand how Myc inhibits adipogenesis, we analyzed the effect of Myc on the expression of genes characteristic of distinct phases of the hormonally induced adipo genic differentiation program in 3T3-L1 preadipocytes. We show that the ear ly regulators, C/EBP beta and C/EBP delta, are induced normally in response to hormone in 3T3-L1 preadipocytes constitutively expressing Myc, but that expression of the downstream regulators, C/EBP alpha and PPAR gamma 2, and later markers of differentiation is suppressed. These data demonstrate tha t Myc specifically inhibits the terminal stages of the adipogenic program a nd suggest that Myc may act by blocking C/EBP beta- and C/EBP delta-directe d activation of C/EBP alpha and PPAR gamma 2 expression, although the preci se molecular mechanism is not understood. Surprisingly, a serum component(s ) could override the Myc-induced differentiation block, suggesting that the ability of a cell to undergo terminal differentiation is governed by the a ction of both positive and negative factors. Since differentiation and prol iferation are mutually exclusive events, this has important implications si nce it may be possible to force malignant cells along a differentiation pat hway, thereby curbing their proliferative potential. (C) 2000 Academic Pres s.