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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5199-5207.
Prepublished online as a Blood First Edition Paper on February 22, 2007; DOI 10.1182/blood-2006-11-059378.
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Submitted November 27, 2006
Accepted February 15, 2007
Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization
Andrew G Muntean, Liyan Pang, Mortimer Poncz, Steven F Dowdy, Gerd A Blobel, and John D Crispino*
Graduate Program in Molecuar Genetics and Cell Biology, University of Chicago, Chicago, IL, United States
Division of Hematology, Children's Hospital of Pennsylvania, Philadelphia, PA, United States
Howard Hughes Medical Institute, University of California San Diego, San Diego, CA, United States
Division of Hematology/Oncology, Northwestern University, Chicago, IL, United States
* Corresponding author; email: j-crispino{at}northwestern.edu.
Endomitosis is a unique form of cell cycle utilized by megakaryocytes, where the latter stages of mitosis are bypassed so that the cell can increase its DNA content and size. Although several transcription factors, including GATA-1 and RUNX-1, have been implicated in this process, the link between transcription factors and polyploidization remain undefined. Here we show that GATA-1 deficient megakaryocytes, which display reduced size and polyploidization, express nearly 10-fold less cyclin D1 and 10-fold increased levels of p16 compared to their wild-type counterparts. We further demonstrate that cyclin D1 is a direct GATA-1 target in megakaryocytes, but not erythroid cells. Restoration of cyclin D1 expression, when accompanied by ectopic overexpression of its partner Cdk4, resulted in a dramatic increase in megakaryocyte size and DNA content. However, terminal differentiation was not rescued. Of note, polyploidization was only modestly reduced in cyclin D1-deficient mice, likely due to compensation by elevated cyclin D3 expression. Finally, consistent with an additional defect conferred by increased levels of p16, inhibition of cyclin D/Cdk4 complexes with a TAT-p16 fusion peptide significantly blocked polyploidization of wild-type megakaryocytes. Together, these data show that GATA-1 controls growth and polyploidization by regulating cyclin D/Cdk4 kinase activity.
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