Mef2 and the skeletal muscle differentiation program

Surface-induced crystallization of pharmaceuticals and biopharmaceuticals: A review.

BACKGROUND The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. METHODS The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. CONCLUSIONS This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy.

Cardiovascular development and survival require Mef2c function in the myocardial but not the endothelial lineage.

Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%-80% of cancer patients, depending on the tumor type, and is associated with 20%-40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy-a key feature in cancer cachexia-no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA-mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA-mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies.

https://www.mdpi.com/1422-0067/20/8/1962/pdf

The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis.

Myocyte enhancer factor 2C (MEF2C) is a transcription factor of MADS box family involved in the early development of several human cells including muscle (i.e., skeletal, cardiac, and smooth), neural, chondroid, immune, and endothelial cells. Dysfunction of MEF2C leads to embryo hypoplasia, disorganized myofibers and perinatal lethality. The main role of MEF2C is its regulation of muscle development. It has been reported that MEF2C-knockout mice die on embryonic day 9.5 from unnatural development of cardiovascular. The effects of MEF2C are mediated by its directly-interacting proteins; therefore, the investigation of these interactions is critical in order to clarify MEF2C's biological function. In this study, we review twenty-five proteins that directly interact with MEF2C, including nineteen proteins related to muscle development, four proteins related to neural cell development, one protein related to chondroid cell development, four proteins related to immune cell development, and two proteins related to endothelial cell development. Among these proteins, the interaction of MEF2C with MRFs is important for differentiation of developing muscle cells. MEF2C interacts with Sox18 for endothelial vessel morphogenesis. The interaction of MEF2C with Cabin1 is important for maintaining T-cell inactivation. Investigating the interactions of MEF2C and its directly-interacting proteins is not only helpful to understand of the physiological function of MEF2C, but also provides a target for future rational drug design.

Myocyte enhancer factor 2C and its directly-interacting proteins: A review.

Finding new nucleants to promote protein crystallization is an important task, especially for purposes other than structural determination. Here, we investigated cyclodextrins and its derivative particles, as potential nucleants for protein crystallization. β-cyclodextrin (β-CD) and its derivatives (including p-toluenesulfonyl-β-cyclodextrin (PTCD), polymer-β-cyclodextrin (PCD), Mono-(6-(1,6-hexamethylenediamine)-6-deoxy)-β-Cyclodextrin (MHCD) and Mercapto-β-cyclodextrin (MCD)) were used as nucleants. The experimental results confirmed that β-CD and its derivatives showed significantly positive effects, promoting protein crystallization and improving crystal quality. A larger number of protein molecules (including lysozyme, catalase, subtilisin A VIII, concanavalin A VI, α-chymotrypsinogen, proteinase K, cellulase, papain, glucose isomerase, hemoglobin and ribonuclease A XII) attached to the particles usually corresponded to a higher crystallization success rate. More detailed analysis showed that cyclode...

Utilization of Cyclodextrins and Its Derivative Particles as Nucleants for Protein Crystallization

Protein crystallization is of great importance because protein crystals have a number of different important applications, including large-scale purification of proteins, determination of protein structure, nanoparticle preparation, and theoretical studies of crystallization. An approach often used to efficiently crystallize proteins is the use of nucleants or seeds (small fragments of protein crystals) that can help increase the probability of protein crystallization. Due to the very positive effect that seeding has on protein crystallization, seeds are now widely accepted and utilized in practical protein crystallization. Here, we show that cross-linked protein crystals (CLPCs), which retain the crystal structure but are much more stable than non-cross-linked crystals, can also be used as a new type of seed for promoting protein crystallization. Seeding with CLPCs has effects on both the reproducibility and screening of protein crystals and could improve the optical perfection (well-defined facets) of p...

Seeding Protein Crystallization with Cross-Linked Protein Crystals

The invention provides a method for changing the roughness of a crystalline basement by using a soft lithography chip for protein crystallization The method comprises the following steps: firstly, designing and producing a PDMS (Polydimethylsiloxane) chip meeting the crystallization requirements of protein; secondly, dropwise adding a protein crystallization solution on the surface of the PDMS chip, standing and crystallizing According to the method provided by the invention, by designing the PDMS chip, a controllable crystallization interface with uniform roughness is realized, so that the nucleation probability of the protein on the surface of the basement is improved, and further the aim of improving the success rate of protein crystallization is achieved According to the method, the screening success rate of protein crystallization conditions can be improved by 1 to 5 times

Xue-Zhou Yang

Papers

Myocyte enhancer factor 2C and its directly-interacting proteins: A review.

Utilization of Cyclodextrins and Its Derivative Particles as Nucleants for Protein Crystallization

Seeding Protein Crystallization with Cross-Linked Protein Crystals

Method for changing roughness of crystalline basement by using soft lithography chip for protein crystallization

Expanding pH screening space using multiple droplets with secondary buffers for protein crystallization