ACTA1 isoform is the major component in skeletal muscle thin filament of sarcomere and is essential for force production, muscle contraction and movement [13, 14]
ACTA1 isoform is the major component in skeletal muscle thin filament of sarcomere and is essential for force production, muscle contraction and movement [13, 14]. of overexpressed PAX3-FOXO1 protein. CCG-1423 is an inhibitor of RhoA-MKL1-SRF signaling, we observed there was a synergistic effect between this inhibitor and to suppress reporter activity. Furthermore, overexpression decreased protein level and knockdown of by siRNA enhanced expression. In addition, both MKL1 and SRF, but not RhoA were also found to be inhibited by gene at protein levels and increased once knockdown of expression. The association between MKL1 and SRF in cells was decreased accordingly with ectopic expression of PAX3-FOXO1. However, the distribution of MKL1 and SRF in nuclear or cytoplasm fraction was not changed by expression. Finally, we showed that overexpression in RH30 cells could inhibit cell proliferation and migration in vitro and impair tumor growth in vivo compared with the control groups. Conclusions is inhibited by at transcription and protein levels through RhoA-MKL1-SRF signaling pathway and this inhibition may partially contribute to the tumorigenesis and development of ARMS. Our findings improved the understanding of in ARMS and provided a potential strategy for the treatment of ARMS in future. (RMS) is the most common soft tissue tumor in children and young adults with an incidence of about six cases per 1,000,000 population per year [1, 2]. (ERMS) and (ARMS) are the two major morphologic subtypes of RMS characterized on the basis of their clinical and histopathological features [3, 4]. ERMS is more common and favorable to treatment than ARMS. In contrast, BMS-817378 ARMS is more aggressive and BMS-817378 has a worse outcome than ERMS. Specifically, most ARMS are characterized by chromosomal translocation of either t (2; 13) (q35; q14) or t (1; 13) (q36; q14), mainly generating and fusion genes, respectively. These fusion genes encode chimeric proteins PAX3/7-FOXO1, which consist of the N-terminal DNA-binding domain of PAX3/7 and the C-terminus of the transactivation domain of FOXO1 protein [5, 6]. Both PAX3-FOXO1 and PAX7-FOXO1 are expressed at higher levels and have more potent transcriptional activities than the wild types of PAX3/7 proteins in ARMS tumors. But is more common accounting for about 55% of ARMS cases than with 22% of ARMS and is associated with worse prognosis and lower overall survival rate in this disease [7C9]. Numerous studies have shown that is oncogenic and involved in ARMS tumorigenesis [10C12]. Exogenous expression of could cause the transformation of chicken embryo fibroblast cells to become enlarged and grow in multiple layers . In the study using immortalized human myoblast, cells expressing PAX3-FOXO1 protein developed tumor in immunocompromised mice . Knockdown of expression by siRNA oligonucleotide in ARMS cells reduced the cell motility, inhibited the rate of cellular proliferation and induced the muscle differentiation . However, the detailed mechanism of implicated in ARMS tumorigenesis is still not fully understood. Skeletal muscle alpha-actin protein (ACTA1), encoded by gene, belongs to the actin protein family consisting of six isoforms in human . ACTA1 isoform is the major component in skeletal Mouse monoclonal to FAK muscle thin filament of sarcomere and is essential for force production, muscle BMS-817378 contraction and movement [13, 14]. expression is developmentally and transcriptionally regulated in vivo. In chicken skeletal muscle, vascular actin (ACTA2) is the first muscle actin to be expressed in the myotome, then ACTA2 is downregulated and cardiac actin (ACTC) expression increases. At the time of birth, cardiac actin expression is downregulated and ACTA1 expression is increased and remains the major isoform in adult skeletal muscle [15, 16]. A similar developmental process occurs for in human skeletal muscle [17, 18]. At the transcriptional level, expression is mainly modulated by serum response factor (SRF) [19, 20]. SRF is a MADS-box transcription factor that is highly conserved and ubiquitously expressed and can regulate muscle-specific gene expression by binding to the CC(A/T)6GG consensus sequence (also called CArG box) within the promoter region of target genes . SRF controls transcription and expression by binding to CArG box and associating with the coactivator myocardin-related transcription factor A (MRTF-A/MKL1/Mal/BSAC). MKL1 is one member of the MRTF family which consists of myocardin, MKL1.