The notch regulator MAML1 interacts with p53 and functions as a coactivator.
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.
Zhao
Yongtong
Y
Division of Cancer Biology, Department of Medicine, ENH Research Institute, Feinberg School of Medicine, Northwestern University, Evanston, Illinois 60201, USA.
Katzman
Rebecca B
RB
Delmolino
Laurie M
LM
Bhat
Ishfaq
I
Zhang
Ying
Y
Gurumurthy
Channabasavaiah B
CB
Germaniuk-Kurowska
Aleksandra
A
Reddi
Honey V
HV
Solomon
Aharon
A
Zeng
Mu-Sheng
MS
Kung
Aisha
A
Ma
Hui
H
Gao
Qingshen
Q
Dimri
Goberdhan
G
Stanculescu
Adina
A
Miele
Lucio
L
Wu
Lizi
L
Griffin
James D
JD
Wazer
David E
DE
Band
Hamid
H
Band
Vimla
V
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*
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