TUMOR NECROSIS FACTOR-INDUCED C-MYC EXPRESSION IN THE ABSENCE OF MITOGENESIS IS ASSOCIATED WITH INHIBITION OF ADIPOCYTE DIFFERENTIATION

Tumor necrosis factor (TNF) inhibits and reverses differentiation of m ouse adipogenic TA1 cells. We have found that TNF induces c-myc in a s ustained manner in both preadipocytes and adipocytes; in contrast, ser um induces c-myc transiently and only in preadipocytes. This TNF-media ted c-myc induction is not coupled with cell proliferation but is corr elated with TNF-mediated inhibition of adipocyte differentiation. We p repared an inducible c-myc transformant of TA1 cells by transfection o f the mouse c-myc gene under the control of the metallothionein-I prom oter. These cells are unable to differentiate to adipocytes in the pre sence of Zn2+/Cd2+, and in differentiated TA1 cells, Zn2+/Cd2+ causes reduction of adipocyte-specific gene expression as does TNF. Lastly, e xposure of TA1 cells to antisense c-myc oligonucleotide partially bloc ked the TNF-mediated reduction of adipocyte-specific gene expression. Thus, TNF-mediated c-myc expression is distinct in character from that involved in mitogenic responses but appears to play an important role in inhibition and reversal of adipocyte differentiation.