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J. Biol. Chem., Vol. 282, Issue 16, 11969-11981, April 20, 2007

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The Notch Regulator MAML1 Interacts with p53 and Functions as a Coactivator^*

Yongtong Zhao, Rebecca B. Katzman¹, Laurie M. Delmolino², Ishfaq Bhat², Ying Zhang³, Channabasavaiah B. Gurumurthy², Aleksandra Germaniuk-Kurowska, Honey V. Reddi, Aharon Solomon^¶, Mu-Sheng Zeng, Aisha Kung, Hui Ma, Qingshen Gao, Goberdhan Dimri, Adina Stanculescu^||, Lucio Miele^||, Lizi Wu^**, James D. Griffin^**, David E. Wazer, Hamid Band^¶4, and Vimla Band, Recipient of support from the Duckworth family through the Duckworth Family Chair for Breast Cancer Research⁵

From the Cancer Biology and ^¶Molecular Oncology, Department of Medicine, ENH Research Institute, Feinberg School of Medicine, and Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60201, the Department of Radiation Oncology, New England Medical Center, Boston, Massachusetts 02111, the ^||Breast Cancer Program and Department of Pharmacology and Experimental Therapeutics, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Chicago, Illinois 60153, and the ^**Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Members of the evolutionarily conserved Mastermind (MAM) protein family, including the three related mammalian Mastermind-like (MAML) proteins MAML1–3, function as crucial coactivators of Notch-mediated transcriptional activation. Given the recent evidence of cross-talk between the p53 and Notch signal transduction pathways, we have investigated whether MAML1 may also be a transcriptional coactivator of p53. Indeed, we show here that MAML1 is able to interact with p53. We show that MAML1-p53 interaction involves the N-terminal region of MAML1 and the DNA-binding domain of p53, and we use a chromatin immunoprecipitation assay to show that MAML1 is part of the activator complex that binds to native p53-response elements within the promoter of the p53 target genes. Overexpression of wild-type MAML1 as well as a mutant, defective in Notch signaling, enhanced the p53-dependent gene induction in mammalian cells, whereas MAML1 knockdown reduced the p53-dependent gene expression. MAML1 increases the half-life of p53 protein and enhances its phosphorylation/acetylation upon DNA damage of cells. Finally, RNA interference-mediated knockdown of the single Caenorhabditis elegans MAML homolog, Lag-3, led to substantial abrogation of p53-mediated germ-cell apoptotic response to DNA damage and markedly reduced the expression of Ced-13 and Egl-1, downstream pro-apoptotic targets of the C. elegans p53 homolog Cep-1. Thus, we present evidence for a novel coactivator function of MAML1 for p53, independent of its function as a coactivator of Notch signaling pathway.

Received for publication, September 20, 2006 , and in revised form, February 9, 2007.

^* This work was supported in part by National Institutes of Health Grants CA94143, CA96844, CA81076 (to V. B.), CA87986, CA76118, CA99900, and CA99163 (to H. B.). 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.

¹ Recipient of National Institutes of Health postdoctoral fellowship of Signal Transduction and Cancer Training Grant T32CA70085.

² Supported by the Department of Defense Postdoctoral Traineeship Grant DAMD-17-03-1-0585.

³ Recipient of Carol and Marvin Gollob Fellowship.

⁴ Supported by the Jean Ruggles-Romoser Chair for Cancer Research.

⁵ To whom correspondence should be addressed: Division of Cancer Biology, ENH Research Institute, 1001 University Place, Evanston, IL 60201. Tel.: 224-364-7501; Fax: 224-364-7402; E-mail: v-band{at}northwestern.edu.

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