TY - JOUR
T1 - The Notch regulator MAML1 interacts with p53 and functions as a coactivator
AU - Zhao, Yongtong
AU - Katzman, Rebecca B.
AU - Delmolino, Laurie M.
AU - Bhat, Ishfaq
AU - Zhang, Ying
AU - Gurumurthy, Channabasavaiah B.
AU - Germaniuk-Kurowska, Aleksandra
AU - Reddi, Honey V.
AU - Solomon, Aharon
AU - Zeng, Mu Sheng
AU - Kung, Aisha
AU - Hui, Ma
AU - Gao, Qingshen
AU - Dimri, Goberdhan
AU - Stanculescu, Adina
AU - Miele, Lucio
AU - Wu, Lizi
AU - Griffin, James D.
AU - Wazer, David E.
AU - Band, Hamid
AU - Band, Vimla
PY - 2007/4/20
Y1 - 2007/4/20
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M608974200
DO - 10.1074/jbc.M608974200
M3 - Article
C2 - 17317671
AN - SCOPUS:34249740225
SN - 0021-9258
VL - 282
SP - 11969
EP - 11981
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 16
ER -