Shen H, McElhinny AS, Cao Y, Gao P, Liu J, Bronson R et al.. The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. Genes Dev 20: 675-688

Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes & Development (Impact Factor: 10.8). 04/2006; 20(6):675-88. DOI: 10.1101/gad.1383706
Source: PubMed


The MAML (mastermind-like) proteins are a family of three co-transcriptional regulators that are essential for Notch signaling, a pathway critical for cell fate determination. Though the functions of MAML proteins in normal development remain unresolved, their distinct tissue distributions and differential activities in cooperating with various Notch receptors suggest that they have unique roles. Here we show that mice with a targeted disruption of the Maml1 gene have severe muscular dystrophy. In vitro, Maml1-null embryonic fibroblasts failed to undergo MyoD-induced myogenic differentiation, further suggesting that Maml1 is required for muscle development. Interestingly, overexpression of MAML1 in C2C12 cells dramatically enhanced myotube formation and increased the expression of muscle-specific genes, while RNA interference (RNAi)-mediated MAML1 knockdown abrogated differentiation. Moreover, we determined that MAML1 interacts with MEF2C (myocyte enhancer factor 2C), functioning as its potent co-transcriptional regulator. Surprisingly, however, MAML1's promyogenic effects were completely blocked upon activation of Notch signaling, which was associated with recruitment of MAML1 away from MEF2C to the Notch transcriptional complex. Our study thus reveals novel and nonredundant functions for MAML1: It acts as a coactivator for MEF2C transcription and is essential for proper muscle development. Mechanistically, MAML1 appears to mediate cross-talk between Notch and MEF2 to influence myogenic differentiation.

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Available from: Roderick Bronson, Jan 13, 2015
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    • "(c) Fluorescent microscopic image of HEK293 cells co-transfected with vector constructs and miRNA mimics (d). MAML1 (Shen et al. 2006) and IGF-1R (Huang et al. 2011) in older subjects. In general, the inhibition of these genes by miR-133a during muscular growth and development is required for normal muscle development. "
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    ABSTRACT: Age-dependent decline in skeletal muscle function leads to several inherited and acquired muscular disorders in elderly individuals. The levels of microRNAs (miRNAs) could be altered during muscle maintenance and repair. We therefore performed a comprehensive investigation for miRNAs from five different periods of bovine skeletal muscle development using next-generation small RNA sequencing. In total, 511 miRNAs, including one putatively novel miRNA, were identified. Thirty-six miRNAs were differentially expressed between prenatal and postnatal stages of muscle development including several myomiRs (miR-1, miR-206 and let-7 families). Compared with miRNA expression between different muscle tissues, 14 miRNAs were up-regulated and 22 miRNAs were down-regulated in the muscle of postnatal stage. In addition, a novel miRNA was predicted and submitted to the miRBase database as bta-mir-10020. A dual luciferase reporter assay was used to demonstrate that bta-mir-10020 directly targeted the 3'-UTR of the bovine ANGPT1 gene. The overexpression of bta-mir-10020 significantly decreased the DsRed fluorescence in the wild-type expression cassette compared to the mutant type. Using three computational approaches - miranda, pita and rnahybrid - these differentially expressed miRNAs were also predicted to target 3609 bovine genes. Disease and biological function analyses and the KEGG pathway analysis revealed that these targets were statistically enriched in functionality for muscle growth and disease. Our miRNA expression analysis findings from different states of muscle development and aging significantly expand the repertoire of bovine miRNAs now shown to be expressed in muscle and could contribute to further studies on growth and developmental disorders in this tissue type. © 2015 Stichting International Foundation for Animal Genetics.
    Full-text · Article · Feb 2015 · Animal Genetics
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    • ", mRpL48, frtz, Rim2, Eno, Rrp40, CG31937, CG17652, CG17646, CG17712, CG17648, Gr22f, CG17650, Gr22-(e-a), CG31933 Candidate suppressors (21E4;21F1): asteroid, Atg4a, CG4692, MtRNApol, CG14339, CG14340, Pino, CG4552, Iris, CG4577, MFS3, CG4749, Tfb4, Vsp29, capulet (continued) mam. In vivo studies in mammalian models have shown that the mam ortholog Mastermind-Like 1 (Maml1) encodes a transcriptional cofactor that physically interacts with Mef2 to augment Mef2-dependent promyogenic signaling (Shen et al. 2006; Potthoff and Olson 2007). Similar to D-Mef2, mam loss-of-function mutation dominantly suppressed PAX7-FOXO12induced lethality (Figure 5B). "
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    ABSTRACT: Rhabdomyosarcoma (RMS) is an aggressive childhood malignancy of neoplastic muscle-lineage precursors that fail to terminally differentiate into syncytial muscle. The most aggressive form of RMS, Alveolar-RMS (A-RMS), is driven by misexpression of the PAX-FOXO1 oncoprotein, which is generated by recurrent chromosomal translocations that fuse either the PAX3 or PAX7 gene to FOXO1. The molecular underpinnings of PAX-FOXO1-mediated RMS pathogenesis remain unclear, however, and clinical outcomes poor. Here, we report a new approach to dissect RMS, exploiting a highly efficient Drosophila PAX7-FOXO1 model uniquely configured to uncover PAX-FOXO1 RMS genetic effectors in only one generation. With this system, we have performed a comprehensive deletion screen against the Drosophila autosomes, and demonstrate that mutation of Mef2, a myogenesis lynchpin in both flies and mammals, dominantly suppresses PAX7-FOXO1 pathogenicity and acts as a PAX7-FOXO1 gene target. Additionally, we reveal that mutation of mastermind, a gene encoding a MEF2 transcriptional co-activator, similarly suppresses PAX7-FOXO1, further pointing towards MEF2 transcriptional activity as a PAX-FOXO1 underpinning. These studies show the utility of the PAX-FOXO1 Drosophila system as a robust one-generation (F1) RMS gene discovery platform and demonstrate how Drosophila transgenic conditional expression models can be configured for the rapid dissection of human disease. Copyright © 2014 Author et al.
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    • "In the nucleus, the Notch intracellular domain (Notch ICD) associates with the transcription factor CSL (also known as RBP-Jk or CBF1 in vertebrates, Suppressor of Hairless in Drosophila and Lag-1 in C. elegans) when it is bound to DNA, and coactivators such as PCAF [3], GCN5 [3], p300 [4] and MAML1 [1], [2] are recruited to activate the expression of Notch target genes. Recently, MAML1 has been shown to function as a coactivator for transcription factors involved in a variety of Notch-independent signaling pathways, including myocyte enhancer factor 2C (MEF2C) [5], p53 [6] and beta-catenin [7], and the N-terminus of MAML1 is crucial for these interactions. These findings suggest that MAML1 functions as a coactivator in diverse cellular processes and may be a mediator of crosstalk between different signaling pathways. "
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    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.
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