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

• Published in: Cell cycle (Georgetown, Tex.) Vol. 14; no. 10; pp. 1517 - 1528
• Main Authors: Badodi, Sara, Baruffaldi, Fiorenza, Ganassi, Massimo, Battini, Renata, Molinari, Susanna
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2015
• Subjects: 14-3-3 Proteins - metabolism; Amino Acid Sequence; Anaphase-Promoting Complex-Cyclosome - metabolism; Animals; Antigens, Differentiation - metabolism; Cadherins - antagonists & inhibitors; Cadherins - genetics; Cadherins - metabolism; Cdc20 Proteins - antagonists & inhibitors; Cdc20 Proteins - genetics; Cdc20 Proteins - metabolism; Cell Proliferation; Cyclin B1 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Down-Regulation; G2 Phase Cell Cycle Checkpoints; HEK293 Cells; Humans; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Molecular Sequence Data; NIH 3T3 Cells; Phosphorylation; Sequence Alignment; MEF2; HDAC, Histone Deacetylases; proliferation; cell cycle; CHX, Cycloheximide; MyHC, Myosin Heavy Chain; degradation; CDK, Cyclin Dependent Kinase; Gadd45b, Growth Arrest and DNA Damage b; mitosis; APC/C, Anaphase Promoting Complex/Cyclosome; APC/C; CRC, ColoRectal Cancer; MEF2, Myocyte Enhancer Factor 2; degron, degradation signal; muscle; splicing; MADS, Minichromosome maintenance, Agamous, Deficiens, Serum response factor; phosphorylation; UPS, Ubiquitin Proteasome System
• ISSN: 1538-4101; 1551-4005
• DOI: 10.1080/15384101.2015.1026519

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 α1 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 (14-3-3γ, 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.