Previous and current research
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 regulated by association with different cofactors. The Ternary Complex Factor (TCF) family of Ets domain proteins - SAP-1, Elk-1 and Net - are controlled through MAP kinase signal pathways. In contrast, members of the Myocardin Related Transcription Factor (MRTF) family - MAL/MKL1, MAL16/MKL2 and myocardin - are either regulated through Rho GTPase signalling (MAL and MAL16), or apparently act constitutively (Myocardin). Our current research on the SRF system focuses on the molecular analysis of these regulatory cofactors, and their role in processes controlled by Rho GTPases, such as adhesion and motility. Research on the TCF family is aimed at the elucidation of the SAP-1 gene to developmental processes. A developing research interest in the laboratory is the role played by SRF and its cofactors in T cell development and immune function.
Future projects
Regulation of SRF activity by Rho GTPases occurs through their ability to induce changes in actin dynamics, specifically depletion of the G-actin pool. We recently showed that the MAL protein associates with G-actin through a novel sequence motif, and its accumulation in the cell nucleus is induced by changes in actin dynamics. Several studies will address molecular aspects of MAL regulation, including:
- detailed analysis of MAL/actin and MAL/SRF interactions;
- elucidation of the mechanism by which MAL is imported into and re-exported from the nucleus;
- determination of the function of signal-induced phosphorylation of MAL;
- analysis of regulatory differences between MAL family members.
Other projects in this area will include the investigation of actin dynamics in other signal-regulated processes. Using both knockout and siRNA approaches to manipulate cofactor function, we will assess the importance of Rho-actin and TCF signalling for SRF target gene expression and cellular behaviour in vivo. Using knockouts we have also shown that the SAP-1 protein is essential for efficient selection of both CD4- and CD8-single positive T cells. Future experiments will focus on in-depth analysis of the roles of both the TCFs and the MAL/MAL16 family in development and function of immune system, and characterisation of other aspects of the SAP-1 phenotype. We will also investigate their role in tumour cell proliferation and spread.
