title: Myocardin-related transcription factor A regulates expression of Bok and Noxa and is involved in apoptotic signalling.
abstract: The myocardin-related transcription factor MAL/MRTF-A relates changes in G-actin to SRF-mediated gene expression. The set of G-actin-controlled SRF target genes includes components of the cytoskeleton and cell migration machinery as well as various signal transducers. Our previous screen for G-actin regulated genes identified a number of targets with well-established anti-proliferative and proapoptotic functions. Here, we report that the two proapoptotic Bcl-2 family members Bok and Noxa/Pmaip are directly transcriptionally induced by activated MAL and upon activation of the actin-MAL-SRF pathway. This activation depends on MRTFs and is sensitive to the actin drug latrunculin but insensitive to p53 depletion. A cis-regulatory element comprising a CArG-like box in the Bok promoter is required and inducibly recruits MAL and SRF. Moreover, MAL/MRTF-dependent transcriptional activity and target gene expression is upregulated upon stimulation of fibroblasts with TNF and staurosporin. This is accompanied by nuclear accumulation of MRTFs. The results suggest a role for MAL in TNF signaling and implicate the MAL-SRF transcription module in regulating the proapoptotic Bcl-2 family network.
authors.affiliation: AG Regulation of Gene Expression, Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shaposhnikov
authors.forename: Arnaud
authors.initials: A
authors.lastname: Descot
authors.forename: Johannes
authors.initials: J
authors.lastname: Schilling
authors.forename: Guido
authors.initials: G
authors.lastname: Posern
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005786:Gene Expression Regulation; D051379:Mice; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000378:metabolism; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000199:Actins; C111858:Bok protein, mouse; C511173:Mrtfa protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C503315:myocardin-related transcription factor B, mouse; D019311:Staurosporine