title: The notch regulator MAML1 interacts with p53 and functions as a coactivator.
abstract: 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.
authors.affiliation: Division of Cancer Biology, Department of Medicine, ENH Research Institute, Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201, USA.
authors.forename: Yongtong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Katzman
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Delmolino
authors.forename: Ishfaq
authors.initials: I
authors.lastname: Bhat
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Channabasavaiah B
authors.initials: CB
authors.lastname: Gurumurthy
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Germaniuk-Kurowska
authors.forename: Honey V
authors.initials: HV
authors.lastname: Reddi
authors.forename: Aharon
authors.initials: A
authors.lastname: Solomon
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Aisha
authors.initials: A
authors.lastname: Kung
authors.forename: Hui
authors.initials: H
authors.lastname: Ma
authors.forename: Qingshen
authors.initials: Q
authors.lastname: Gao
authors.forename: Goberdhan
authors.initials: G
authors.lastname: Dimri
authors.forename: Adina
authors.initials: A
authors.lastname: Stanculescu
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Lizi
authors.initials: L
authors.lastname: Wu
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: David E
authors.initials: DE
authors.lastname: Wazer
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; C504038:Ced-13 protein, C elegans; D004268:DNA-Binding Proteins; C112486:EGL-1 protein, C elegans; C430872:MAML1 protein, human; D009687:Nuclear Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C409224:SEL-8 protein, C elegans; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53