Mitotic clonal expansion: A s required for adipogenesis
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When induced to differentiate, growth-arrested 3T3-L1 preadipo- va cytes synchronously reenter the cell cycle and undergo mitotic pr clonal expansion (MCE) followed by expression of genes that produce the adipocyte phenotype. The preadipocytes traverse the re G1/S checkpoint synchronously as evidenced by the expression/ pc activation of cdk2-cyclin-E/A, turnover of p27/kip1, hyperphos- ad phorylation of Rb, translocation of cyclin D1 from nuclei to cytoplasm and GSK-3P3 from cytoplasm to nuclei, and incorporation of [3H]thymidine into DNA. As the cells cross the G1/S checkpoint, T\ C/EBPp acquires DNA-binding activity, initiating a cascade of 31 transcriptional activation that culminates in the expression of st< adipocyte proteins. The mitogen-activated protein kinase/extra- wi cellular signal-regulated kinase kinase (MEK) inhibitor PD98059 im delays, but does not block, MCE and differentiation, the extent of co the delay causing a comparable delay in the expression of cell-cycle ex markers, MCE, and adipogenesis. The more potent and specific SI MEK inhibitor U0126 and the cyclin-dependent kinase inhibitor (c' roscovitine, which inhibit the cell cycle at different points, block mi MCE, expression of cell cycle and adipocyte markers, as well as (I adipogenesis. These results show that MCE is a prerequisite for (L differentiation of 3T3-L1 preadipocytes into adipocytes. ra (L cell cycle I adipogenesis I 3T3-L1 preadipocyte I C/EBPa I PPARy m
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