SRF Co-factors Control the Balance between Cell Proliferation and Contractility
Open accessAbstract
The ERK-regulated ternary complex factors (TCFs) act with the transcription factor serum response factor (SRF) to activate mitogen-induced transcription. However, the extent of their involvement in the immediate-early transcriptional response, and their wider functional significance, has remained unclear. We show that, in MEFs, TCF inactivation significantly inhibits over 60% of TPA-inducible gene transcription and impairs cell proliferation. Using integrated SRF ChIP-seq and Hi-C data, we identified over 700 TCF-dependent SRF direct target genes involved in signaling, transcription, and proliferation. These also include a significant number of cytoskeletal gene targets for the Rho-regulated myocardin-related transcription factor (MRTF) SRF cofactor family. The TCFs act as general antagonists of MRTF-dependent SRF target gene expression, competing directly with the MRTFs for access to SRF. As a result, TCF-deficient MEFs exhibit hypercontractile and pro-invasive behavior. Thus, competition between TCFs and MRTFs for SRF determines the balance between antagonistic proliferative and contractile programs of gene expression.
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MRTFs are direct effectors of growth factors through ERK signalling.
“Proliferation of hepatocytes during liver regeneration is known to be sustained by YAP/TAZ signalling [6] but MRTFs are direct effectors of growth factors through ERK signalling [33]; the Myc gene showed an increase in our CCl4 models.”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [33]
The Introduction and the Results section ‘TPA Treatment Both Activates and Downregulates Gene Transcription’ identify TCFs, not MRTFs, as mediators of the ERK-induced response in mouse embryonic fibroblasts. The Results also report that ERK-activating TPA did not activate a classical MRTF-SRF target gene. Page numbers are unavailable in our copy. (LLM, conf=0.89)
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Experimental — accuracy not yet measuredGenes related to cell adhesion, cytoskeleton and extracellular matrix components are well-known targets of MRTcoF.
“Genes related to cell adhesion, cytoskeleton and ECM components are well‐known targets of MRTcoF [9, 33].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [33]
The Discussion says MRTF-SRF signaling regulates genes involved in cytoskeletal dynamics, and the Introduction links MRTFs to adhesive processes. The Results identify MRTF-SRF target genes, but the passages do not establish extracellular matrix components as a category of their targets. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThere is an important relationship between proliferation and lipid metabolism mediated by SRF signalling.
“There is an important relationship between proliferation and lipid metabolism mediated by SRF signalling [33].”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [33]
The Introduction says TCF-dependent SRF target genes are associated with metabolism and proliferation, and the Results report impaired proliferation in TCF-deficient mouse embryonic fibroblasts. Neither passage identifies lipid metabolism specifically, so the claimed relationship with lipid metabolism is not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTUBB and DUSP genes are reported recurrently as positive target genes for MRTcoF.
“First, we chose TUBB and DUSP genes, reported recurrently as positive target genes for MRTcoF [10, 11, 33] (Fig. 3A,B and Fig. S4B).”
From Mechanical stiffness orchestrates distinct regulation of <scp>MRTFs</scp> and <scp>YAP</scp> / <scp>TAZ</scp> transcriptional cofactors in hepatocytes (2026) · cites this paper as [33]
The Results section on TCF binding and MRTF-SRF signaling names Acta2, Ctgf, and Dstn as MRTF-SRF targets, while the section defining TCF-dependent targets describes a shared MRTF-TCF gene set. Neither passage identifies TUBB or DUSP genes as positive MRTF-cofactor targets; searches for Tubb and Dusp found no passage establishing that claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured
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Cites
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“Pro-invasive behavior is associated with hypercontractility in cancer-associated fibroblasts (Calvo et al., 2013; Gaggioli et al., 2007).”
BackgroundIterative correction of Hi-C data reveals hallmarks of chromosome organization
Imakaev, M., Fudenberg, G., McCord, R. P., Naumova, N., Goloborodko, A., Lajoie, B. R., Dekker, J., & Mirny, L. A. (2012) · Nature Methods · doi:10.1038/nmeth.2148 · Cited by 1,423 · see citing works
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“Re-expression of wild-type Elk-1 but not the transcriptionally inactive mutants Elk-1nonA and Elk-1DFW (Balamotis et al., 2009; Buchwalter et al., 2004, 2005) restored significant TPA-inducibility to many Direct and Indirect TCF target genes (Figures 4A and 4B; Table S5).”
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- Authors
- Gualdrini, F., Esnault, C., Horswell, S., Stewart, A., Matthews, N., & Treisman, R.
- Affiliations
- The Francis Crick Institute (GB)
- Corresponding author
- Treisman, Richard
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 64
- Issue
- 6
- Pages
- 1048-1061
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5179500
- OpenAlex
- W2549182437
- Cited by
- 161
- References
- 6
- Citations by year
- 2026: 6 · 2025: 20 · 2024: 21 · 2023: 15 · 2022: 33 · 2021: 19 · 2020: 16 · 2019: 11 · 2018: 11 · 2017: 8
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Funders
- Cancer Research UK (FC001-190)
- Francis Crick Institute
- UK Medical Research Council (FC001-190)
- Wellcome Trust (FC001-190)
- ERC Advanced Grant (268690 ACTINonSRF)
- EMBO (ALTF 872-2008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- serum response factor, ternary complex factor, MRTF, cell proliferation, cell contractility, immediate early gene expression, Rho GTPase signaling, cell invasion
- MeSH terms
- Animals, Base Sequence, Cell Line, Fibroblasts, Gene Expression Regulation, Genetic Complementation Test, Humans, Tetradecanoylphorbol Acetate, Transcription, Genetic, Signal Transduction, Trans-Activators, Gene Expression Profiling, Serum Response Factor, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Ternary Complex Factors, ets-Domain Protein Elk-1, Mice
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