Richard Treisman

Signalling and Transcription Laboratory

We study the mechanisms by which cellular signal transduction pathways cause specific activation of gene transcription. We focus on the transcriptional regulator SRF, first identified through our studies of the c-fos proto-oncogene, which controls both growth factor-regulated and muscle-specific genes.

SRF activity is controlled through its association with two families of regulatory cofactors. The Ternary Complex Factor (TCF) family of Ets proteins - SAP-1, Elk-1 and Net - are controlled by phosphorylation of their C-terminal activation domains by MAP kinases. In contrast, members of the Myocardin Related Transcription Factor (MRTF) family - MRTF-A/MAL/MKL1, MRTF-B/MKL2 and myocardin - are either regulated through Rho GTPase signalling (MRTF-A and MRTF-B), or act constitutively (Myocardin). The MRTFs are novel G-actin binding proteins, which sense changes in cellular G-actin concentration through their N-terminal RPEL domains.

 

The Rho-actin signal pathway.

The Rho-actin signal pathway. Activation of Rho GTPase signalling induces changes in actin treadmilling resulting in depletion of the cellular G-actin pool. This causes changes in the stoichiometry or amount of G-actin-RPEL protein complex, and changes in its activity. (Click to view larger image)

Our current research on the SRF system focuses on the molecular analysis of the regulatory cofactors, and their role in Rho- and Ras-dependent processes including cell proliferation, adhesion and motility in both cancer and immune cell contexts. A subsidiary interest in the lab concerns the analysis of other RPEL proteins, including the Phactr family of PP1 cofactors, whose activity is subject to control by variations in G-actin concentration.

We use approaches ranging from biochemistry, structural biology and cell biology to studies of cancer and immune mouse models in knockout mice. Our current studies focus on a number of areas:

  • SRF cofactor recruitment is gene-specific, and we are investigating the molecular basis for cofactor recruitment to SRF target genes.
  • We are using genomic approaches to assess the significance of signalling for events in transcriptional initiation and chromatin modification downstream of the MRTF and TCF cofactors.
  • The MRTF actin-binding RPEL domain controls nuclear import and export, phosphorylation, transcriptional activation, and possibly SRF interaction. We use structural, cell biological and biochemical approaches to study these regulatory events.
  • The role of the SRF network and Rho-actin signalling in cell behaviour, particularly cancer cell proliferation, invasion and metastasis.
  • Other potential roles of actin as a regulatory factor, focussing on the regulation Phactr family of RPEL domain proteins, and two new families of novel RPEL proteins.
  • Mice lacking the SRF network have severe defects in T cell development and function. We are using this system to investigate functional redundancy between the TCFs, and the connections between MAP kinase signalling, transcription, and cell differentiation.

Selected publications

Esnault, C., Stewart, A., East, P., Horswell, S., Mathews, N., Gualdrini, F. and Treisman, R. (2014) Rho-actin signalling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes and Development 28: 943-58.

Wiezlak, M., Diring, J., Abella, J., Mouilleron S., Way, M., McDonald, N.Q., and Treisman, R (2012) The RPEL protein Phactr1 exploits actin-regulated nucleocytoplasmic shuttling and PP1 binding to regulate actomyosin contractility. J Cell Sci 125, 5860-5872.

Mouilleron S, Langer CA, Guettler S, McDonald NQ, Treisman R. (2011) Structure of a Pentavalent G-Actin:MRTF-A Complex Reveals How G-Actin Controls Nucleocytoplasmic Shuttling of a Transcriptional Coactivator. Sci Signal. 4(177):ra40

Mylona A, Nicolas R, Maurice D, Sargent M, Tuil D, Daegelen D, Treisman R, Costello P.The essential function for SRF in T cell development reflects its specific coupling to ERK signalling. (2010) Mol and Cell Biol. 31(2):267-76

Costello P, Nicolas R, Willoughby J, Wasylyk B, Nordheim A, Treisman R. (2010) Ternary complex factors SAP-1 and Elk-1, but not net, are functionally equivalent in thymocyte development. J Immunol. 185(2):1082-92

Vartiainen MK, Guettler S, Larijani B, Treisman R. (2007) Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science. 316(5832):1749-52

Miralles F, Posern G, Zaromytidou AI, Treisman R. (2003) Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113:329-342

Richard Treisman

richard.treisman@crick.ac.uk
+44 (0) 20 7269 3271

  • Qualifications and history
  • 1981 PhD, Imperial Cancer Research Fund/University College London, UK (Advisor: Bob Kamen)
  • 1981 Postdoctoral Fellow, Harvard University, USA (Advisor: Tom Maniatis)
  • 1984 Scientific Staff, MRC Laboratory of Molecular Biology, UK
  • 1988 Established lab at the Imperial Cancer Research Fund (ICRF; became Cancer Research UK in 2002)
  • 2000 Director of Laboratory Research, ICRF
  • 2002 Director, London Research Institute, Cancer Research UK
  • 2009 Research Director, the Francis Crick Institute, London, UK