Objective
Regulation of normal development and tissue function is the product of a balanced interplay between the mechanisms that regulate cell division, differentiation and cell death. Whereas the molecular mechanisms leading to cell growth and their contribution to cell transformation have been extensively explored in the last two decades, much less is known about the mechanisms that inhibit cell growth, most particularly in function of the adhesion status of the cell. Furthermore, simultaneous activation of the growth stimulatory and growth inhibitory programmes may raise cellular conflict leading to cell death, both in normal as well as in tumour cells. The overall aim of this integrated proposal is to define the factors which modulate key genes in the control of cell cycle arrest and cell death. The proto-oncogene c-myc and the tumour suppresser gene p53 have been shown to be major players in the control of normal cell proliferation and the development of malignancies. Activation of c-myc in quiescent cells is sufficient for induction of DNA synthesis whereas, activation of p53 prevents entry of cycling cells into S phase, but also renders them susceptible to apoptosis. Recent evidence suggests that extra-cellular matrix plays a protective role against apoptosis. Interestingly, one of the key cell cycle regulators of the G1/S transit, cyclin A has an expression which is strongly induced by c-myc, but also dependent upon cell anchorage. TGFbeta, a pleiotropicytokine that negatively regulates cell growth of mainly epithelial cells, induces a subset of the immediate early genes, notably Jun B, and represses some of the cell cycle regulators, such as cyclin A, through a signal transduction cascade which is presently almost completely obscure. However, whereas growth factors stimulate the expression of extra-cellular metalloproteinases collagenase and stromelysin, TGFbeta inhibits their expression and could thus interfere with apoptosis.
We plan to study TGFbeta receptor signalling as well as the effect of TGFbeta on c-myc-induced cyclin A expression, DNA synthesis and apoptosis in p53+/+ and p53-/- contexts. The regulation of the expression and the interplay of the selected players : c-myc, Jun B and cyclin A will be analysed at both the transcriptional and post-transcriptional levels. In the latter we will investigate changes in sub-cellular localisation of both c-myc and cyclin A mRNAs, and investigate changes in the mRNA-cytoskeleton interactions and localisation in response to TGFbeta.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
33033 Montpellier
France
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