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J. Biol. Chem., Vol. 283, Issue 23, 15589-15600, June 6, 2008

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Tumor Suppressor Protein p53 Regulates Megakaryocytic Polyploidization and Apoptosis^*

Peter G. Fuhrken¹, Pani A. Apostolidis², Stephan Lindsey, William M. Miller, and Eleftherios T. Papoutsakis³

From the Department of Chemical and Biological Engineering, Northwestern University, Evanston, Illinois 60208 and the Department of Chemical Engineering and the Delaware Biotechnology Institute, University of Delaware, Newark, Delaware 19711

The molecular mechanisms underlying differentiation of hematopoietic stem cells into megakaryocytes are poorly understood. Tumor suppressor protein p53 can act as a transcription factor affecting both cell cycle control and apoptosis, and we have previously shown that p53 is activated during terminal megakaryocytic (Mk) differentiation of the CHRF-288-11 (CHRF) cell line. Here, we use RNA interference to reduce p53 expression in CHRF cells and show that reduced p53 activity leads to a greater fraction of polyploid cells, higher mean and maximum ploidy, accelerated DNA synthesis, and delayed apoptosis and cell death upon phorbol 12-myristate 13-acetate-induced Mk differentiation. In contrast, reduced p53 expression did not affect the ploidy or DNA synthesis of CHRF cells in the absence of phorbol 12-myristate 13-acetate stimulation. Furthermore, primary Mk cells from cultures initiated with p53-null mouse bone marrow mononuclear cells displayed higher ploidy compared with wild-type controls. Quantitative reverse transcription-PCR analysis of p53-knockdown CHRF cells, compared with the "scrambled" control CHRF cells, revealed that six known transcriptional targets of p53 (BBC3, BAX, TP53I3, TP53INP1, MDM2, and P21) were down-regulated, whereas BCL2 expression, which is known to be negatively affected by p53, was up-regulated. These studies show that the functional role of the intrinsic activation of p53 during Mk differentiation is to control polyploidization and the transition to endomitosis by impeding cell cycling and promoting apoptosis.

Received for publication, March 10, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL48276. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Supported by a National Science Foundation Graduate Research Fellowship.

² Supported by the A. S. Onassis Foundation.

³ To whom correspondence should be addressed: Delaware Biotechnology Institute, University of Delaware, 15 Innovation Way, Newark, DE 19711. Fax: 302-831-4841; E-mail: papoutsakis{at}dbi.udel.edu.

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