The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Nucleic Acids Research (Impact Factor: 9.11). 04/2009; 37(9):2996-3006. DOI: 10.1093/nar/gkp163
Source: PubMed


MAML1 is a transcriptional coregulator originally identified as a Notch coactivator. MAML1 is also reported to interact with
other coregulator proteins, such as CDK8 and p300, to modulate the activity of Notch. We, and others, previously showed that
MAML1 recruits p300 to Notch-regulated genes through direct interactions with the DNA–CSL–Notch complex and p300. MAML1 interacts
with the C/H3 domain of p300, and the p300–MAML1 complex specifically acetylates lysines of histone H3 and H4 tails in chromatin
in vitro. In this report, we show that MAML1 potentiates p300 autoacetylation and p300 transcriptional activation. MAML1 directly
enhances p300 HAT activity, and this coincides with the translocation of MAML1, p300 and acetylated histones to nuclear bodies.

Download full-text


Available from: Beverley Marie Dancy, Aug 15, 2014
  • Source
    • "EGR1 alone activated the p300-luc reporter in the presence of TPA, and co-transfection of MAML1 with EGR1 strongly increased the activity of the p300 reporter (Figure 3A). We hypothesized that MAML1 may regulate the expression of p300, as well as the acetylation activity of p300 [11]. Lysates were prepared from a FLAG-MAML1 cell line and HEK-293 control cells, and the levels of p300 were analyzed by Western blotting using an antibody recognizing p300. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mastermind-like 1 (MAML1) is a transcriptional coregulator of activators in various signaling pathways, such as Notch, p53, myocyte enhancer factor 2C (MEF2C) and beta-catenin. In earlier studies, we demonstrated that MAML1 enhanced p300 acetyltransferase activity, which increased the acetylation of Notch by p300. In this study, we show that MAML1 strongly induced acetylation of the transcription factor early growth response-1 (EGR1) by p300, and increased EGR1 protein expression in embryonic kidney cells. EGR1 mRNA transcripts were also upregulated in the presence of MAML1. We show that MAML1 physically interacted with, and acted cooperatively with EGR1 to increase transcriptional activity of the EGR1 and p300 promoters, which both contain EGR1 binding sites. Bioinformatics assessment revealed a correlation between p300, EGR1 and MAML1 copy number and mRNA alterations in renal clear cell carcinoma and p300, EGR1 and MAML1 gene alterations were associated with increased overall survival. Our findings suggest MAML1 may be a component of the transcriptional networks which regulate EGR1 target genes during nephrogenesis and could also have implications for the development of renal cell carcinoma.
    Full-text · Article · Sep 2012 · PLoS ONE
  • Source
    • "Thus, we concluded that SIRT1 deacetylase activity altered the endothelial Notch signaling cascade by deacetylating N1IC and antagonizing p300. Hansson et al. showed that MAML1 (Notch coactivator) could potentiate p300 autoacetylation and p300 transcriptional activation [19]. However, our results suggest that SIRT1 physically interacts with and represses p300 transactivation in an NAD-dependent manner. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sirtuin 1 (SIRT1) acts as a key regulator of vascular endothelial homeostasis, angiogenesis, and endothelial dysfunction. However, the underlying mechanism for SIRT1-mediated lung carcinoma angiogenesis remains unknown. Herein, we report that the nicotinamide adenine dinucleotide 1 (NAD1)-dependent deacetylase SIRT1 can function as an intrinsic negative modulator of Delta-like ligand 4 (DLL4)/Notch signaling in Lewis lung carcinoma (LLC) xenograft-derived vascular endothelial cells (lung cancer-derived ECs). SIRT1 negatively regulates Notch1 intracellular domain (N1IC) and Notch1 target genes HEY1 and HEY2 in response to Delta-like ligand 4 (DLL4) stimulation. Furthermore, SIRT1 deacetylated and repressed N1IC expression. Quantitative chromatin immunoprecipitation (qChIP) analysis and gene reporter assay demonstrated that SIRT1 bound to one highly conserved region, which was located at approximately -500 bp upstream of the transcriptional start site of Notch1,and repressed Notch1 transcription. Inhibition of endothelial cell growth and sprouting angiogenesis by DLL4/Notch signaling was enhanced in SIRT1-silenced lung cancer-derived EC and rescued by Notch inhibitor DAPT. In vivo, an increase in proangiogenic activity was observed in Matrigel plugs from endothelial-specific SIRT1 knock-in mice. SIRT1 also enhanced tumor neovascularization and tumor growth of LLC xenografts. Our results show that SIRT1 facilitates endothelial cell branching and proliferation to increase vessel density and promote lung tumor growth through down-regulation of DLL4/Notch signaling and deacetylation of N1IC. Thus, targeting SIRT1 activity or/and gene expression may represent a novel mechanism in the treatment of lung cancer.
    Preview · Article · Sep 2012 · PLoS ONE
  • Source
    • "Instead, we used a mouse strain that expresses a dominant negative form of Master-mind-like (DN-MAML) under the control of the ROSA26 locus after hGFAP-driven-Cre-induced recombination. MAML proteins bind the NICD/RBP-J complex and act as scaffolds to recruit coactivators, such as p300 (Fryer et al., 2002; Hansson et al., 2009). The DN-MAML lacks its activation domain to recruit transcriptional coactivators and blocks Notch signaling from all four Notch receptors (Tu et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: During brain development, neurons and glias are generated from neural stem cells and more limited intermediate neural progenitors (INPs). Numerous studies have revealed the mechanisms of development of neural stem cells. However, the signaling pathways that govern the development of INPs are largely unknown. The cerebellum is suitable for examining this issue because cerebellar cortical inhibitory neurons such as basket and stellate cells are derived from small Pax2(+) interneuronal progenitors. Here, we show that Sox2(-)/Pax2(+) and Sox2(+)/Pax2(-) progenitors, 2 types of interneuronal progenitors of basket and stellate cells, exist in the cerebellar white matter (WM) and that the former arise from the latter during the first postnatal week. Moreover, RBP-J promotes the neurogenesis of stellate and basket cells by converting Sox2(+)/Pax2(-) interneuronal progenitors to more mature Sox2(-)/Pax2(+) interneuronal progenitors. This study shows a novel RBP-J function that promotes INP differentiation.
    Full-text · Article · Mar 2011 · Developmental Biology
Show more