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Molecular and Cellular Biology, June 2003, p. 4230-4246, Vol. 23, No. 12
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.12.4230-4246.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Molecular Basis of p53 Functional Inactivation by the Leukemic Protein MLL-ELL

Dmitri Wiederschain,1,2 Hidehiko Kawai,1 JiJie Gu,1 Ali Shilatifard,3 and Zhi-Min Yuan1,2*

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115,1 Ph.D. Program in Biological Sciences in Public Health, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts 02138,2 Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, Missouri 631043

Received 5 November 2002/ Returned for modification 17 December 2002/ Accepted 18 March 2003

The Eleven Lysine-rich Leukemia (ELL) gene undergoes translocation and fuses in frame to the Multiple Lineage Leukemia (MLL) gene in a substantial proportion of patients suffering from acute forms of leukemia. Molecular mechanisms of cellular transformation by the MLL-ELL fusion are not well understood. Although both MLL-ELL and wild-type ELL can reduce functional activity of p53 tumor suppressor, our data reveal that MLL-ELL is a much more efficient inhibitor of p53 than is wild-type ELL. We also demonstrate for the first time that ELL extreme C terminus [ELL(eCT)] is required for the recruitment of p53 into MLL-ELL nuclear foci and is both necessary and sufficient for the MLL-ELL inhibition of p53-mediated induction of p21 and apoptosis. Finally, our results demonstrate that MLL-ELL requires the presence of intact ELL(eCT) in order to disrupt p53 interactions with p300/CBP coactivator and thus significantly reduce p53 acetylation in vivo. Since ELL(eCT) has recently been shown to be both necessary and sufficient for MLL-ELL-mediated transformation of normal blood progenitors, our data correlate ELL(eCT) contribution to MLL-ELL transformative effects with its ability to functionally inhibit p53.

* Corresponding author. Mailing address: Department of Cancer Cell Biology, Bldg. 1, Rm. 509, 665 Huntington Ave., Boston, MA 02115. Phone: (617) 432-0763. Fax: (617) 432-0377. E-mail: zyuan{at}hsph.harvard.edu.

Molecular and Cellular Biology, June 2003, p. 4230-4246, Vol. 23, No. 12
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.12.4230-4246.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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