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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.
Submitted July 15, 2003
Accepted October 6, 2003
Identification of the molecular requirements for an RAR 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*
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Division of Clinical Haematology/Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; Department of Medicine, Univeristy of Melbourne, St. Vincent's Hospital, Fitzroy, VIC, Australia
Department of Chemistry, Allergan Inc., Irvine, CA, USA
Department of Biology, Allergan Inc., Irvine, CA, USA
Institute of Medical Science, University of Tokyo, Tokyo, Japan
Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP/College de France, Illkirch, France
* Corresponding author; email: grant.mcarthur{at}petermac.org.
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 utilized myeloid differentiation to characterise the molecular pathways that couple cell cycle withdrawal to terminal differentiation. Using primary cells from mice deficient for either the CDKi p27Kip1, the Myc-antagonist Mad1 or both Mad1 and p27Kip1 we observed that signals mediated through Retinoic Acid Receptor  (RAR), but not RAR or  , required both Mad1 and p27Kip1 to induce cell cycle arrest and to accelerate terminal differentiation of granulocytes. While RAR did not directly regulate Mad1 or p27Kip1, the RAR-target gene C/EBP directly regulated transcription of Mad1. Induction of C/EBP activity in granulocytic cells led to rapid induction of Mad1 protein and transcript, with direct binding of C/EBP to the Mad1 promoter as demonstrated by ChIP assay. These data demonstrate that cell cycle arrest in response to RAR specifically requires Mad1 and p27Kip1 and that Mad1 is transcriptionally activated by C/EBP. Moreover, these data demonstrate selectivity amongst 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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