The Role of Stat3 in Adipocytic Differentiation
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Cellular proliferation is often regulated in conjunction with differentiation. It is important to investigate the mechanisms underlying cellular differentiation and proliferation, because defects in their control can promote neoplastic transformation. 3T3L1 preadipocytes provide a good cell culture model to study differentiation, since they differentiate into fat pads when injected into nude mice. Previous data have suggested that Signal Transducer and Activator of Transcription-3 (Stat3) is activated during 3T3L1 differentiation, and may be directly promoting adipogenesis. However, our lab recently demonstrated that engagement of cadherins, as occurs during confluence of cultured cells, triggers a dramatic surge in Stat3 activity, constituting a potent survival signal. Since confluence-mediated, growth arrest is a prerequisite for adipocytic differentiation, the question arises as to the role of Stat3 in adipocytic differentiation of 3T3L1 cells. This work has shown that levels of Stat3 activity increase in 3T3L1 cells, with or without the induction of differentiation. Nevertheless, Stat3 activation was, in fact, higher in differentiating cells compared to control preadipocytes at the same density, and correlated with expression of adipocyte binding protein 2 (aP2), indicating that Stat3 may play a role in differentiation. 3T3L1 cells expressing the constitutively active Stat3C protein displayed moderate increases in differentiation compared to parental 3T3L1 cells. Inhibition of Stat3 with CPA7 at confluence blocked the onset of differentiation, and caused both control and differentiating cells to undergo apoptosis, while inhibition of Stat3 after differentiation was induced had no distinct effect. These results point to the possibility that besides its potential role in differentiation, Stat3 plays an important role in survival of differentiating 3T3L1 preadipocytes.