Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid‐induced pre‐B lymphoma cell apoptosis

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Abstract
Cip/Kip family protein p21, a cyclin‐dependent kinase (CDK) inhibitor, is directly transactivated by retinoic acid receptor alpha (RARα) upon retinoic acid (RA):RARα binding. Yet the role of p21 upregulation by RA in lymphoma cells remains unknown. Here, we show that, in human pre‐B lymphoma Nalm6 cells, RA‐induced proliferation inhibition results from massive cell death characterized by apoptosis. Upregulated p21 by RA accompanies caspase‐3 activation and precedes the occurrence of apoptosis. p21 induction leads to increased p21 complex formation with cyclin E/CDK2, which occurs when cyclin E and CDK2 levels remain constant. CDK2 can alternatively promote apoptosis, but the mechanisms remain unknown. Data presented here suggest a novel RA‐signaling, by which RA‐induced p21 induction and complex formation with cyclin E/CDK2 diverts CDK2 function from normally driving proliferation to alternatively promoting apoptosis.