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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-11-059378v1 109/12/5199    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Muntean, A. G. Articles by Crispino, J. D. Search for Related Content PubMed PubMed Citation Articles by Muntean, A. G. Articles by Crispino, J. D. Related Collections Cell Cycle Gene Expression Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Cyclin D–Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization Andrew G. Muntean1, Liyan Pang2, Mortimer Poncz2, Steven F. Dowdy3, Gerd A. Blobel2, and John D. Crispino4,5 1 Graduate Program in Molecular Genetics and Cell Biology, University of Chicago, IL; 2 Children's Hospital of Pennsylvania, Philadelphia; 3 Howard Hughes Medical Institute, University of California San Diego; 4 Ben May Department for Cancer Research, University of Chicago, IL; 5 Division of Hematology/Oncology, Northwestern University, Chicago, IL Endomitosis is a unique form of cell cycle used by megakaryocytes, in which 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 remains 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 with 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. J. McCrann, T. Yezefski, H. G. Nguyen, N. Papadantonakis, H. Liu, Q. Wen, J. D. Crispino, and K. Ravid Survivin overexpression alone does not alter megakaryocyte ploidy nor interfere with erythroid/megakaryocytic lineage development in transgenic mice Blood, April 15, 2008; 111(8): 4092 - 4095. [Abstract] [Full Text] [PDF] L. Gilles, R. Guieze, D. Bluteau, V. Cordette-Lagarde, C. Lacout, R. Favier, F. Larbret, N. Debili, W. Vainchenker, and H. Raslova P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1 Blood, April 15, 2008; 111(8): 4081 - 4091. [Abstract] [Full Text] [PDF]

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