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MRTF/SRF signalling in regulation of cell senescence and melanoma progression

Project description

Modulating cell senescence for therapeutic benefit

Cell senescence is a natural process tightly linked with ageing, development and tissue repair, where cells undergo cell cycle arrest and may trigger the recruitment of immune cells. In cancer, cell senescence is also responsible for acquired drug resistance, tumour progression and metastasis. The EU-funded MRTFSen project aims to provide mechanistic insight into the process by focussing on the role of myocardin-related transcription factors (MRTFs). MRTFs, in association with the transcription factor serum response factor (SRF), act as transcriptional co-activators to transduce cytoskeletal signals to the nucleus and promote myogenic differentiation and cytoskeletal organisation. Scientists will investigate the molecular mechanisms by which MRTF-SRF signalling inhibits cell senescence, unveiling potential senescence pathway targets with therapeutic value.

Objective

Myocardin-related transcription factors (MRTFs) are G-actin binding proteins which act as transcriptional co-activators Myocardin-related transcription factors (MRTFs) are G-actin binding proteins which act as transcriptional co-activators in association with the transcription factor SRF. MRTF-SRF target genes encode numerous proteins involved in actin dynamics, cell adhesion, migration and contractility. The subcellular localization of the MRTFs is controlled by actin binding which inhibits their nuclear import and promotes their nuclear export. Extracellular signals which activate Rho-family GTPases induce actin polymerization and G-actin depletion, which induces MRTF shuttling to the nucleus and transcriptional activation of MRTF-SRF target genes. The MRTF-SRF pathway activation via Rho plays an important role in cancer cell invasion and metastasis. In addition, in MRTF-SRF signalling inhibits cell senescence in hepatocarcinoma cells which present high Rho activity, but this has not been investigated in other cell types or cancer models. Cell senescence is a process of cell-cycle arrest which typically occurs in ageing, cancer, development or tissue repair, and can facilitate recruitment of immune cells. In the tumour microenvironment, senescent cells can direct events such as therapeutic resistance or metastasis that support malignant progression. In this project we will determine the molecular mechanisms by which MRTF-SRF signalling inhibits cell senescence in MEFs. We also aim to investigate the possibility for it to modulate melanoma progression in the BRafV600E mouse model, where senescence is an initial step prior tumour transformation. Increasing evidence suggests that anti- and pro-senescent therapies can be beneficial also in other pathologies, such as fibrosis, by limiting cell proliferation and allowing clearance of damaged cells. These studies have the potential to reveal new approaches to the modulation of senescence pathways for therapeutic benefit.

Coordinator

THE FRANCIS CRICK INSTITUTE LIMITED
Net EU contribution
€ 224 933,76
Address
1 MIDLAND ROAD
NW1 1AT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Research Organisations
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Total cost
€ 224 933,76