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Regulation of lymphocyte development and activation by RNA binding proteins and non-coding RNA

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The rapid changes in gene expression that accompany developmental transitions, stress responses and proliferation are controlled by signal-mediated co-ordination of transcriptional and post-transcriptional mechanisms. The synthesis of new RNA with the capacity to encode proteins or with regulatory potential is a keystone event in these processes. Of equal importance is the regulation of RNA stability and localisation (on translating ribosomes or elsewhere in the cell). Thus the dynamics of gene expression involve the integration of transcription and post-transcriptional control by signal transduction networks. Understanding the mechanics of these processes and the contexts in which they are employed during haematopoiesis and immune challenge is a goal towards which important progress has been made in recent years. A significant aspect of the progress is the recognition of the importance of non-coding RNA in the development and function of the immune system. Non-coding RNA includes microRNAs, but also the untranslated regions of messenger RNAs which function by binding microRNAs and also proteins which recognise specific sequences or secondary structures. I will discuss specific examples of post-transcriptional control in the regulation of lymphocytes development and activation.

Martin Turner was a PhD student with Marc Feldmann where he studied the regulation of cytokine gene expression. Amongst these studies was the observation that TNF induced IL-1, a basic finding that contributed to the rationale of anti-TNF therapy. Next, with Victor Tybulewicz he applied mouse genetics to understand the signaling mechanisms of the lymphocyte antigen receptors. This work highlighted the roles of the kinase Syk and of Vav1. Subsequently, he has identified roles for phosphoinositide 3-kinase (PI3K) pathways in lymphocyte development and function. He has published key studies on the role of P110delta in B lymphocyte signalling pathways. These studies have contributed to the knowledge base underpinning the successful use of isoform-selective PI3 Kdelta inhibitors in the clinic for the treatment of chronic lymphocytic leukaemia. He has pioneered the investigation of post-transcriptional regulation of lymphocyte development function identifying physiological roles for microRNAs and RNA binding proteins (RBPs) in the differentiation of B and T lymphocytes. These studies have also provided clear evidence for a tumour suppressor role mediated by RBPs.

This talk is part of the Foster Talks series.

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