Identification of the molecular requirements for an RARα-mediated cell cycle arrest during granulocytic differentiation

Retinolds are potent inducers of cell cycle arrest and differentiation of numerous cell types, notably granulocytes. However the mechanisms by which retinoids mediate cell cycle arrest during differentiation remain unclear. We have used myeloid differentiation to characterize the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the cyclin-dependent kinase inhibitor (CDKi) p27Kip1, the Myc antagonist Mad1, or both Madl and p27(Kip1), we observed that signals mediated through reti-sponse to RARalpha specifically requires Mad1 and p27(Kip1) and that Mad1 is transcriptionally activated by CCAAT/ enhancer-binding protein E (C/EBPE). Moreover, these data demonstrate selectivity among the RARs for cell cycle arrest pathways and provide a direct mechanism to link differentiation induction and regulation of the Myc antagonist Mad1. (C) 2004 by The American Society of Hematology.