TNF-ALPHA DISRUPTS MITOTIC CLONAL EXPANSION AND REGULATION OF RETINOBLASTOMA PROTEINS P130 AND P107 DURING 3T3-L1 ADIPOCYTE DIFFERENTIATION

The inhibitory effects of TNF alpha on adipocyte differentiation are w ell described, however, the mechanisms are poorly understood. Early du ring hormonally-induced 3T3-L1 preadipocyte differentiation there is a requisite mitotic clonal expansion phase that is associated with sign ificant regulation in p130 and p107 protein levels, two members of the retinoblastoma protein family that regulate cell cycle events through interactions with the E2F transcription factors. This regulation occu rs within the first 24 hours of differentiation (Day 1) and is charact erized by a transient increase in p107 protein and mRNA levels as well as a transient decrease in p130 protein levels. Here we describe that TNF alpha disrupts the normal pattern of expression of both p130 and p107 proteins, leading to a complete block in mitotic clonal expansion . Interestingly, TNF alpha-treated cells enter S-phase as determined b y 5-bromo-2'-deoxyuridine uptake experiments, but rather than completi ng cell cycle, they are stimulated to undergo apoptosis. (C) 1998 Acad emic Press.