Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells

Zhang, Meiling; Truscott, Jamie; Davie, Judith K.

doi:10.1186/1476-4598-12-150

Cited by 32 publications

(25 citation statements)

References 49 publications

(62 reference statements)

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“…7G). In agreement with our observations, a recent study demonstrated that ectopically expressed MEF2D can upregulate p21 expression (42). CDKN1A transcription fluctuates during the cell cycle, accumulating in G 0 and showing a peak after serum stimulation (43).…”

Section: Discussionsupporting

confidence: 80%

The Control Operated by the Cell Cycle Machinery on MEF2 Stability Contributes to the Downregulation of CDKN1A and Entry into S Phase

Giorgio

Gagliostro

Clocchiatti

et al. 2015

Molecular and Cellular Biology

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MEF2s are pleiotropic transcription factors (TFs) which supervise multiple cellular activities. During the cell cycle, MEF2s are activated at the G 0 /G 1 transition to orchestrate the expression of the immediate early genes in response to growth factor stimulation. Here we show that, in human and murine fibroblasts, MEF2 activities are downregulated during late G 1 . MEF2C and MEF2D interact with the E3 ligase F-box protein SKP2, which mediates their subsequent degradation through the ubiquitinproteasome system. The cyclin-dependent kinase 4 (CDK4)/cyclin D1 complex phosphorylates MEF2D on serine residues 98 and 110, and phosphorylation of these residues is an important determinant for SKP2 binding. Unscheduled MEF2 transcription during the cell cycle reduces cell proliferation, whereas its containment sustains DNA replication. The CDK inhibitor p21/ CDKN1A gene is a MEF2 target gene required to exert this antiproliferative influence. MEF2C and MEF2D bind a region within the first intron of CDKN1A, presenting epigenetic markers of open chromatin. Importantly, H3K27 acetylation within this regulative region depends on the presence of MEF2D. We propose that following the initial engagement in the G 0 /G 1 transition, MEF2C and MEF2D must be polyubiquitylated and degraded during G 1 progression to diminish the transcription of the CDKN1A gene, thus favoring entry into S phase. In vertebrates, the family of MEF2s comprises 4 members-MEF2A, -B, -C, and -D-as well as some splicing variants (1). Common features of all MEF2 members are the MADS box (MCM1, agamous, deficiens, serum response factor) and the adjacent MEF2 domain positioned within the highly conserved amino-terminal region (1). These domains are involved in recognizing the YTA(A/T) 4 TAR DNA motif, in mediating the formation of homo-and heterodimers, and in the interaction with different cofactors (1). The carboxy-terminal half is much less conserved. It encompasses the transactivation domains and the nuclear localization signal (2). The different family members exhibit specific but also overlapping patterns of expression, during either embryogenesis or adult life (1, 3). MEF2s are subjected to intense supervision by environmental signals, in order to couple the gene expression signature to the organism requirements (1). MEF2s oversee the expression of several genes, depending on and in cooperation with other transcription factors (TFs) (3, 4). In addition, MEF2s can also operate as repressors of transcription when in complexes with class IIa histone deacetylases (HDACs) (5,6,7,8).The extent of genes under the influence of MEF2s justifies the pleiotropic activities and the assorted cellular responses attributed to these TFs. During development, in general, expression of MEF2 is linked to the activation of differentiation programs (1). In various scenarios, the onset of MEF2 expression coincides with the withdrawal from the cell cycle (9). Specific ablation of MEF2C in neural/progenitor cells impacts differentiation but not their survival or proliferation (...

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Section: Discussionsupporting

confidence: 80%

The Control Operated by the Cell Cycle Machinery on MEF2 Stability Contributes to the Downregulation of CDKN1A and Entry into S Phase

Giorgio

Gagliostro

Clocchiatti

et al. 2015

Molecular and Cellular Biology

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“…During the course of this work, we found that both RD and RH30 cells highly expressed MEF2C (29), although MEF2C has also been reported to be down-regulated in RD cells (28). MEF2C has been shown to play an important role in myogenesis, and MEF2C is subject to alternative splicing by exclusion/ inclusion of exon ␣1/2, exon ␤, and exon ␥ (Fig.…”

Section: The Muscle-specific ␣2 Exon Of Mef2c Is Not Expressed In Rmsmentioning

confidence: 71%

“…We chose a musclespecific reporter that contains the Leiomodin2 (Lmod2) pro- moter fused to luciferase, Lmod2-luc, which we have used previously to characterize the activity of the MRFs and MEF2D (29,34). The Lmod2-luc reporter shows very low activity in proliferating cells and is strongly up-regulated upon differentiation.…”

Section: The Muscle-specific ␣2 Exon Of Mef2c Is Not Expressed In Rmsmentioning

confidence: 99%

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Alternative Splicing of MEF2C pre-mRNA Controls Its Activity in Normal Myogenesis and Promotes Tumorigenicity in Rhabdomyosarcoma Cells

Zhang

Zhu

Davie

2015

Journal of Biological Chemistry

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Background: MEF2C is an important regulator of many developmental programs. Results: Alternative splicing of the ␣ exon of MEF2C regulates myogenesis. Loss of SRPK3 in rhabdomyosarcoma cells inhibits this splicing and blocks differentiation. Conclusion: MEF2C␣2 promotes myogenesis, and restoration of MEF2C␣2 in rhabdomyosarcoma cells inhibits growth. Significance: Defining the function and deregulation of MEF2C␣2 enhances the understanding of normal myogenesis and RMS tumorigenesis.

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“…Altered MEF2 activity serves a role in human diseases and it has recently been implicated in the initiation and progression of various types of cancer in humans (31). Recently, it was reported that MEF2D, one member of MEF2 family, is involved in the progression of several cancer types, including lung carcinoma (27), rhabdomyosarcoma (32), hepatocellular carcinoma (31) and osteosarcoma (25).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‑30a is associated with proliferation and invasion via targeting MEF2D in cervical cancer

Zhao

Shu

et al. 2017

Oncol Lett

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Abstract. Accumulating studies have revealed that microRNAs serve crucial roles in cancer development and progression. MicroRNA-30a (miR-30a) has been implicated in various cancer types. However, the role of miR-30a in cervical cancer remains unclear. In the current study, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay revealed that miR-30a was significantly downregulated in cervical cancer tissues compared with adjacent normal tissues, and in the cervical cancer cell lines HeLa, SiHa and Ca-Ski compared with GH329 normal cervical epithelial cells. A functional assay using miR-30a mimic demonstrated that miR-30a could inhibit the growth and invasion of cervical cancer cells. Additionally, bioinformatics-based prediction and luciferase reporter assays indicated that MEF2D is a direct target of miR-30a. Transfection with miR-30a reduced the mRNA expression and protein levels of MEF2D, as determined using RT-qPCR and western blot analyses. Furthermore, MEF2D expression was negatively correlated with that of miR-30a in cervical cancers. Overall, the present study demonstrated that miR-30a functions as a tumor suppressor by targeting MEF2D in cervical cancer, which may provide the basis for a prognostic biomarker or therapeutic strategy for cervical cancer.

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Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells

Cited by 32 publications

References 49 publications

The Control Operated by the Cell Cycle Machinery on MEF2 Stability Contributes to the Downregulation of CDKN1A and Entry into S Phase

The Control Operated by the Cell Cycle Machinery on MEF2 Stability Contributes to the Downregulation of CDKN1A and Entry into S Phase

Alternative Splicing of MEF2C pre-mRNA Controls Its Activity in Normal Myogenesis and Promotes Tumorigenicity in Rhabdomyosarcoma Cells

Downregulation of miR‑30a is associated with proliferation and invasion via targeting MEF2D in cervical cancer

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