The target genes downstream of Actin-MAL signal transduction: The role of differentially regulated transcripts in proliferation and apoptosis
Final Report Abstract
The MRTF-SRF transcription factor module regulates genes involved in a range of functional processes. The repertoire of MRTF target genes was recently broadened by a microarray screen and includes genes involved in apoptosis and proliferation. We explored the regulation of two pro-apoptotic genes, Bok and Noxa, by the MRTF-SRF pathway. Chromatin immunoprecipitation and quantitative realtime PCR showed that Bok is a direct target of the pathway, while Noxa is likely to be regulated by MRTFs, although not via serum response elements in the proximal promoter. By employing apoptosis detection assays, we investigated the antiproliferative effects of the constitutively active MRTF-A in fibroblasts and conclude that MRTF-A-induced cell death can be explained at least in part by the activation of apoptosis. However, MRTFs are also required for normal cell proliferation and cell cycle progression in fibroblasts. siRNA-mediated MRTF double knockdown leads to the downregulation of CIP/KIP family members and premature entry into the S phase, coupled with slightly extended G2 phase, as established by quantification of live cell imaging of cell cycle stages. Additionally, an increased formation of nuclear defects during mitosis was observed, which lead to aneuploidisation. The results demonstrate that MRTFs play a role in the regulation of cell proliferation, since both constitutively activated MRTF and its absence impairs the balance between apoptosis and proliferation. Moreover, our work established a previously unknown connection between MRTFs and the regulation of cell cycle progression.
Publications
- (2009): Negative regulation of the EGFR-MAPK cascade by actin-MAL mediated Mig6/Errfi-1 induction. Mol. Cell 35 (3), 291-304
Descot A., Hoffmann R., Shaposhnikov D., Reschke M., Ullrich A. and Posern G.
- (2010): Epithelial Protein Lost in Neoplasm α (Eplin-α) is transcriptionally regulated by G-actin and MAL/MRTF coactivators. Mol. Cancer 9 (1), 60
Leitner L., Shaposhnikov D., Descot A., Hoffmann R. and Posern G.
- (2011): MAL/MRTF controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins. J. Cell Science 124 (24), 4318-4331
Leitner L., Shaposhnikov D., Mengel A., Descot A., Julien S., Hoffmann R. and Posern G.
- (2011): Should I stall or should I cycle: an inhibitor for Polo-like Kinase 1 with distinct roles in primary cells. Cell Cycle 10 (7), 1029-1030
Posern G.
- (2012): MRTF regulates expression of Bok and Noxa and is involved in apoptotic signalling. Cell Cycle 11 (1), 141-150
Shaposhnikov D., Descot A., Schilling J. and Posern G.
- (2013): Myocardin-related transcription factors are required for coordinated cell cycle progression Cell. Cycle 12 (11), 1762-1772
Shaposhnikov D., Kuffer C., Storchova Z. and Posern G.
(See online at https://doi.org/10.4161/cc.24839)
