Reorganization of the actin cytoskeleton via transcriptional regulation of cytoskeletal/focal adhesion genes by myocardin-related transcription factors (MRTFs/MAL/MKLs).
RhoA is a crucial regulator of stress fiber and focal adhesion formation through the activation of actin nucleation and polymerization. It also regulates the nuclear translocation of myocardin-related transcription factor-A and -B (MRTF-A/B, MAL or MKL 1/2), which are co-activators of serum response factor (SRF). In dominant-negative MRTF-A (DN-MRTF-A)-expressing NIH 3T3 cell lines, the expressions of several cytoskeletal/focal adhesion genes were down-regulated, and the formation of stress fiber and focal adhesion was severely diminished. MRTF-A/B-knockdown cells also exhibited such cytoskeletal defects. In reporter assays, both RhoA and MRTF-A enhanced promoter activities of these genes in a CArG-box-dependent manner, and DN-MRTF-A inhibited the RhoA-mediated activation of these promoters. In dominant-negative RhoA (RhoA-N19)-expressing NIH 3T3 cell lines, the nuclear translocation of MRTF-A/B was predominantly prevented, resulting in the reduced expression of cytoskeletal/focal adhesion proteins. Further, constitutive-active MRTF-A/B increased the expression of endogenous cytoskeletal/focal adhesion proteins, and thereby rescued the defective phenotype of stress fibers and focal adhesions in RhoA-N19 expressing cells. These results indicate that MRTF-A/B act as pivotal mediators of stress fiber and focal adhesion formation via the transcriptional regulation of a subset of cytoskeletal/focal adhesion genes.
Morita
Tsuyoshi
T
Depertment of Neuroscience (D13), Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita, Osaka, Japan.
Mayanagi
Taira
T
Sobue
Kenji
K
D000199:Actins / Q000378:metabolism*; D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism*; D022001:Focal Adhesions / Q000235:genetics*; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D026362:Serum Response Factor / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000199:Actins; C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; C503315:myocardin-related transcription factor B, mouse; D020742:rhoA GTP-Binding Protein