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The role of retinoic acids in apoptosis and cell cycle regulation

Objective



Research objectives and content
Malignant cell growth results from defects in regulation of cell proliferation, differentiation and/or apoptosis. Obviously, such regulatory mechanisms provide potential therapeutic targets of prime importance. Nuclear receptor ligands, in particular steroid (antiestrogens and antiandrogens in breast and prostate cancers, respectively) and retinoid (APL, oral, and head and neck cancers, cervix carcinoma, etc.) receptor ligands are frequently; used in cancer therapy and prevention. These ligands are known to modulate cell proliferation, differentiation and/or apoptosis. However, the way how these ligands trigger regulatory events, by which nuclear receptors control the activities of these key players are largely unknown. This study is focused on the retinoid receptor system. The applicant plans to (i) investigate whether the transcriptional rates of known regulators of cell cycle and apoptosis are controlled through retinoids; (ii) identify novel genes implicated, whose transcription rates are directly regulated through retinoids; (iii) perforrn promotor analysis to reveal direct and indirect regulated events - and finally, (iv) test the cellular specificity of a panel of synthetic retinoids with respect to their activity to induce apoptosis and/or inhibition of cell proliferation, eventually in a tumor-selective fashion. Such insight in molecular mechanisms of signal transduction will pave the way towards novel strategies for therapeutic intervention in cancer.
Training content (objective, benefit and expected impact)
This research project covers training in sophisticated methods to study transcription regulation of cell progression and apoptosis by retinoic acids. A broad spectrum of methodologies will be covered, linking nucleic acid- and protein-based approaches. Experience available at the host institute regarding cell culture and analyzing transcriptional events allow to design direct approaches and learn the required methodology from experienced personnel. Finally this research will help to further intensify skills to study protein/DNA and protein/protein interaction. Overall, this programme will provide the applicant with a highly advanced experience and allow him to perform independent research at his home country. The IGBMC is an institute of high reputation, it offers a forum to meet distinguished scientits and is a top choice for advanced training.
Links with industry / industrial relevance (22)
The group of Dr. Hinrich Gronemeyer has established through various projects (Bl02-CT93-0473; BMH4CT96- 0181) solid contacts with both Schering AB, Berlin, and Roussel-UCLAF, Paris. A long tradition of links to scientific groups working on basic research and clinical aspects of cancer (within the institute as well as at the Universities of Strasbourg and Paris) will enhance the scientific significance and promote the exchange of ideas for research conducted at the IGBMC.

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
France