Myocardin-related transcription factor A regulates expression of Bok and Noxa and is involved in apoptotic signalling

Cell Cycle. 2012 Jan 1;11(1):141-50. doi: 10.4161/cc.11.1.18499. Epub 2012 Jan 1.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Apoptosis*
  • Cell Line
  • Gene Expression Regulation*
  • Mice
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Serum Response Factor / metabolism
  • Signal Transduction
  • Staurosporine / metabolism
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation

Substances

  • Actins
  • Bok protein, mouse
  • Mrtfa protein, mouse
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Serum Response Factor
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • myocardin-related transcription factor B, mouse
  • Staurosporine