MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

Estrella, Nelsa L.; Desjardins, Cody A.; Nocco, Sarah E.; Clark, Amanda; Maksimenko, Yevgeniy; Naya, Francisco J.

doi:10.1074/jbc.m114.589838

Cited by 90 publications

(100 citation statements)

References 48 publications

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“…This has been recently described by a gene expression analysis study in muscle cells. 23 In conclusion our work reveal a novel function of MEF2C beyond its well known role in terminal differentiation. According to the classical model MEF2C does not play any specific function in growing myoblasts but is necessary to trigger the differentiation program upon differentiation stimuli.…”

Section: Discussionmentioning

confidence: 96%

“…[17][18][19][20][21][22] Furthermore, recently Mef2c has been shown to regulate cell cycle related-genes in muscle cells. 23 Therefore, in the attempt to investigate this unexplored activity, we found that the level of MEF2C protein fluctuates during the cell cycle and we describe a novel mechanism by which the Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase controls MEF2C abundance. The functional relevance of this mechanism during the cell cycle is suggested by the observation that ectopic expression of a MEF2C mutant, resistant to APC/C-dependent degradation, impairs entry into mitosis and cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition

et al. 2015

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The Myocyte Enhancer Factor 2C (MEF2C) transcription factor plays a critical role in skeletal muscle differentiation, promoting muscle-specific gene transcription. Here we report that in proliferating cells MEF2C is degraded in mitosis by the Anaphase Promoting Complex/Cyclosome (APC/C) and that this downregulation is necessary for an efficient progression of the cell cycle. We show that this mechanism of degradation requires the presence on MEF2C of a D-box (R-X-X-L) and 2 phospho-motifs, pSer98 and pSer110. Both the D-box and pSer110 motifs are encoded by the ubiquitous alternate a1 exon. These two domains mediate the interaction between MEF2C and CDC20, a co-activator of APC/C. We further report that in myoblasts, MEF2C regulates the expression of G2/M checkpoint genes (14-3-3g, Gadd45b and p21) and the sub-cellular localization of CYCLIN B1. The importance of controlling MEF2C levels during the cell cycle is reinforced by the observation that modulation of its expression affects the proliferation rate of colon cancer cells. Our findings show that beside the well-established role as pro-myogenic transcription factor, MEF2C can also function as a regulator of cell proliferation.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition

et al. 2015

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“…Adenoviruses for Knockdown and Overexpression-Adenoviruses carrying short hairpin RNAs (shRNAs) were generated as described previously (14). The Mef2d and lacZ shRNA adenoviruses were used at a multiplicity of infection of 50 for all assays.…”

Section: Methodsmentioning

confidence: 99%

“…Western Blot Analysis-Western blots were performed as described previously (14). Antibodies included anti-GAPDH (1:1000; Santa Cruz Biotechnology, Inc.), anti-MEF2D (1:1000; BD Biosciences), anti-proliferating cell nuclear antigen (PCNA) (1:2000; Cell Signaling), PTEN (1:1000; Cell Signaling), Akt (1:1000; Cell Signaling), pAkt Thr-308 (1:1000: Cell Signaling), pAkt Ser-473 (1:1000: Cell Signaling), cyclin D1 (1:1000; Cell Signaling), cyclin D3 (1:1000; Cell Signaling), and CDK2 (1:1000; Cell Signaling).…”

Section: Methodsmentioning

confidence: 99%

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MEF2D Deficiency in Neonatal Cardiomyocytes Triggers Cell Cycle Re-entry and Programmed Cell Death in Vitro

Estrella

Clark

Desjardins

et al. 2015

Journal of Biological Chemistry

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Background: Myocyte enhancer factor 2 (MEF2) proteins are key regulators of cardiac muscle differentiation and hypertrophy, but additional roles in this cell type have not been defined. Results: MEF2D regulates the cell cycle and survival of post-mitotic cardiomyocytes. Conclusion: MEF2D is required for proper neonatal cardiomyocyte homeostasis. Significance: These findings provide opportunities to modulate MEF2D activity in cardiomyocyte proliferation and survival.

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BDNF, endurance activity, and mechanisms underlying the evolution of hominin brains

Hill

Polk

2018

American J Phys Anthropol

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ObjectivesAs a complex, polygenic trait, brain size has likely been influenced by a range of direct and indirect selection pressures for both cognitive and non‐cognitive functions and capabilities. It has been hypothesized that hominin brain expansion was, in part, a correlated response to selection acting on aerobic capacity (Raichlen & Polk, 2013). According to this hypothesis, selection for aerobic capacity increased the activity of various signaling molecules, including those involved in brain growth. One key molecule is brain‐derived neurotrophic factor (BDNF), a protein that regulates neuronal development, survival, and plasticity in mammals. This review updates, partially tests, and expands Raichlen and Polk's (2013) hypothesis by evaluating evidence for BDNF as a mediator of brain size.DiscussionWe contend that selection for endurance capabilities in a hot climate favored changes to muscle composition, mitochondrial dynamics and increased energy budget through pathways involving regulation of PGC‐1α and MEF2 genes, both of which promote BDNF activity. In addition, the evolution of hairlessness and the skin's thermoregulatory response provide other molecular pathways that promote both BDNF activity and neurotransmitter synthesis. We discuss how these pathways contributed to the evolution of brain size and function in human evolution and propose avenues for future research. Our results support Raichlen and Polk's contention that selection for non‐cognitive functions has direct mechanistic linkages to the evolution of brain size in hominins.

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MEF2 Transcription Factors Regulate Distinct Gene Programs in Mammalian Skeletal Muscle Differentiation

Cited by 90 publications

References 48 publications

Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition

Phosphorylation-dependent degradation of MEF2C contributes to regulate G2/M transition

MEF2D Deficiency in Neonatal Cardiomyocytes Triggers Cell Cycle Re-entry and Programmed Cell Death in Vitro

BDNF, endurance activity, and mechanisms underlying the evolution of hominin brains

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