The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis

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: 12.64). 04/2006; 20(6):675-88. DOI: 10.1101/gad.1383706
Source: PubMed

ABSTRACT 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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    • "In human myoblasts, Mef2C was suggested to bind directly to the intracellular domain of Notch via the ankyrin repeat region, suppressing Mef2C- induced myogenic differentiation (Wilson-Rawls et al, 1999). Mef2 has also been reported to interact with the Notch coactivator MAML1 and suppress differentiation (Shen et al, 2006). While upregulation of Mef2 alone does not show overt proliferation effects, our analyses demonstrate that in vivo it can activate MMP1. "
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    • "On the other side, the Mastermind-like genes encode critical transcriptional coactivators for Notch signaling. Additionally, the MAML proteins were described as transcriptional coactivators in other signal transduction pathways including muscle differentiation: mice with a targeted disruption of the MAML1 gene had severe muscular dystrophy and MAML1-null embryonic fibroblasts failed to undergo MyoD-induced myogenic differentiation (Shen et al., 2006). Moreover, ectopic MAML1 expression in mouse myoblasts dramatically enhanced myotube formation and increased the expression of muscle-specific genes, while MAML1 knockdown inhibited differentiation. "
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