Document Type

Article

Journal Title

The Journal of biological chemistry

Publication Date

Spring 4-20-2007

Volume

282

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.

MeSH Headings

Animals, Apoptosis, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Cell Line, Tumor, DNA Damage, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphorylation, Receptors, Notch, Repressor Proteins, Signal Transduction, Trans-Activators, Transcription Factors, Transcriptional Activation, Tumor Suppressor Protein p53

ISSN

0021-9258

Rights

This research was originally published in The Journal of Biological Chemistry. Zhao Y, Katzman RB, Delmolino LM, et al. The notch regulator MAML1 interacts with p53 and functions as a coactivator. The Journal of Biological Chemistry. 2007; 282:11969-8. © the American Society for Biochemistry and Molecular Biology."

Download
COinS