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

Abstract

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.

The Ubiquitin Proteome of Toxoplasma gondii Reveals Roles for Protein Ubiquitination in Cell-Cycle Transitions

“…ribosomal proteins) and transmembrane function (Swaney et al, 2013). Phosphorylation is often a prerequisite for ubiquitin-mediated degradation (Badodi et al, 2015). …”

Dynamic Phosphorylation of the Myocyte Enhancer Factor 2Cα1 Splice Variant Promotes Skeletal Muscle Regeneration and Hypertrophy

“…The ability of MEF2Cα1 to promote cell proliferation was also observed in nonmuscle cells such as NIH 3T3 mouse fibroblasts (Supporting Information Fig. C) and colon cancer cells . We used a similar approach to study the role of MEF2Cα1 overexpression on terminal differentiation.…”

NUP98 fusion oncoproteins interact with the APC/CCdc20as a pseudosubstrate and prevent mitotic checkpoint complex binding

“…HEK293 cells were transfected with pBluescript HA6xUbiqui-tine, 33 Flag-NUP98-D13, Flag-NUP98 or Flag-NUP98DPEST. HEK293 were treated with 1 mM MG132 for 16 hours, harvested 48 hours after transfection and lysed in RIPA buffer supplemented with 1 mM PMSF, PIC, 2.5 mM sodium fluoride (NaF), 1 mM sodium orthovanadate (Na3VO4), 0.5 mM EDTA, 10 mM Iodoacetamide, 2 mM MG132 and 1 mM G5, Ubiquitin Isopeptidase Inhibitor I.…”