Research objectives and content
Multiple aspects of growth, development, as well as homeostasis in higher eukaryotes are regulated by ligand-inducible nuclear receptors (NRs), but the mechanisms through which these transcription factors act on basal transcriptional machinery remain largely elusive. "Squelching" observations led to the prediction of NR-associated transcriptional intermediary factors (TIFs, coactivators, corepressors). Amongst recently identified candidate TIFs, only TIF2 and the related SRC-1 proteins possess all the expected characteristics of a TIF.
The proposed project intends to unravel the chain of events by which TIF2 transmits signals to the basal machinery. This involves a three-step strategy: (i) Establishment of a TIF2 functional-domain map to identify an activation-function-conferring fragment (AF) to be used as screening probe. (ii) Expression library screening to clone TIF2 AF-interacting "downstream" factors and additional factors interacting with the TIF2 PAS domain (a possible dimerization function predicted from sequence homology). (iii) Scrutiny of positive clones to track protein-protein interfaces and assess their role in transactivation or in the "cross-talk" with the API complex.
Training content (objective, benefit and expected impact)
Beyond offering the opportunity to become familiar with a number of important methodologies including expression screening and transactivation studies, this project set in the challenging international climate of the IGBMC Strasbourg will particularly strengthen my scientific working skills and help to extend my expertise in the transcription regulation and hormone receptor fields, thus preparing me for future independent research work.
Links with industry / industrial relevance (22)
A deepened understanding of NR-mediated transactivation could pave the way to novel pharmacological targets, namely by interference with the retinoid or estrogen signal transduction pathway. The host group is involved in synthetic hormone assessment in collaboration with Schering, Roussel-Uclaf, and Bristol-Myers-Squibb .