|Enzymatic Regulation of Cellular Activities - CNRS URA2185|
|HEAD||Prof. VERON Michel / email@example.com|
|MEMBERS||Dr AGOU Fabrice / CHIARAVALLI Jeanne / Dr FONTAN Elisabeth / Dr GALETTO Roman
Dr GRUBISHA Olivera / Dr KAMINSKA Monika / Dr NEGRONI Matteo / Dr RAMIREZ Berta Cecilia
SIMON-LORIERE Etienne / TRAINCARD François
NEMO, an essential regulator of the NF-κB signal transduction pathway (PI, Fabrice Agou).
The NF-κB pathway is now recognized to play a crucila role in apoptosis protection and inhibitors are therefore potential proapoptotic anti-cancerous agents. We study NEMO, one of the component of the IKK complex playing a central role in the regulation of the pathway, by combining in vitro structural and biochemical experiments and cell biology approaches. We showed that the oligomerization of NEMO into trimers is necessary for its function. A peptide mimicking the LZ coiled-coil strongly inhibits the activation of the pathway and it also induces apoptosis of malignant cells isolated from myelomas. We have identified the K63 polyubiquitin binding motif of NEMO within the oligomerization domain, providing a functional link between oligomerization and ubiquitin binding in kinase activation within the IKK complex.
NEMO is also involved in several rare human genetical diseases. The functional defects of several mutants recombinant proteins derived from pathologic mutations are characterized.
Recombination in retroviruses: mechanism and evolutionary implications (PI, Matteo Negroni)
Genetic recombination is thought to be involved in various aspects of HIV evolution, by generating forms that do not respond to antiviral treatments, or escape immune control. In retroviruses, reombination results from template switching, during reverse transcription, between the two copies of the genomic RNA present in the viral particle ("copy choice"). Using a reconstituted in vitro system, we first showed that, contrary to the established dogma, the strand exchange was not necessarily due to pauses of reverse transcription but that recombination hot spots were related to the presence of structured regions on the acceptor RNA. Using an original system that allows studying recombination in cell culture after a single infection cycle, we characterised recombinant forms produced in the absence of selection. The crucial role of the structure of the genomic RNA, proposed from in vitro studies, was confirmed in the physiological context of recombination occuring in the infected cell.
We recently begun studying recombinants generated in the env gene starting from primary isolates belonging to different subtypes (groups M & O) of HIV 1 and we are investigating, through functional characterisation of these recombinants, the interplay between the generation and the selection of these recombinant forms.
|More informations on our web site|
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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