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 Blood, 15 February 2004, Vol. 103, No. 4, pp. 1286-1295.
Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-07-2391.

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HEMATOPOIESIS

Identification of the molecular requirements for an RAR{alpha}-mediated cell cycle arrest during granulocytic differentiation

Carl R. Walkley, Louise E. Purton, Hayley J. Snelling, Yang-Dar Yuan, Hideaki Nakajima, Pierre Chambon, Roshantha A. S. Chandraratna, and Grant A. McArthur

From the Division of Research and Division of Clinical Haematology/Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia; Department of Medicine, University of Melbourne, Australia; Retinoid Research, Departments of Chemistry and Biology, Allergan Inc, Irvine, CA; Institute of Medical Science, University of Tokyo, Tokyo, Japan; and Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP/Collège de France, Strasbourg, France.

Retinoids 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 Mad1 and p27Kip1, we observed that signals mediated through retinoic acid receptor {alpha} (RAR{alpha}), but not RAR{beta} or {gamma}, required both Mad1 and p27Kip1 to induce cell cycle arrest and to accelerate terminal differentiation of granulocytes. Although RAR{alpha} did not directly regulate Mad1 or p27Kip1, the RAR{alpha} target gene C/EBP{epsilon} directly regulated transcription of Mad1. Induction of C/EBP{epsilon} activity in granulocytic cells led to rapid induction of Mad1 protein and transcript, with direct binding of C/EBP{epsilon} to the Mad1 promoter demonstrated through chromatin immunoprecipitation assay. These data demonstrate that cell cycle arrest in response to RAR{alpha} specifically requires Mad1 and p27Kip1 and that Mad1 is transcriptionally activated by CCAAT/enhancer-binding protein {epsilon} (C/EBP{epsilon}). 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.


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