Investigating the essential roles of Ubiquitin-like molecules and the Ubiquitin Proteasome System
Our studies aim at a better understanding of the intricate mechanisms by which the ubiquitin-proteasome pathway controls cell proliferation. We follow two main research axes, by a combination of biochemical and cell biology approaches: (i) dissection of the mechanisms regulating the stability of key regulators of cell proliferation, namely the phosphatase CDC25B, cyclin E (CycE) and the oncosuppressive protein p53; (ii) analysis of the functioning and the cellular distribution of the 26S proteasome.
Regarding CDC25B, we recently demonstrated that the protein was particularly unstable at the end of mitosis, and that its uncomplete degradation of CDC25B after metaphase led to unexpected abnormalities. This suggested that unknown substrates of CDC25B were deregulated and our recent work was aimed at their identification. The work on CycE degradation led us to the discovery of a novel mechanism of regulation of the Ubiquitin-ligase responsible for its degradation, the SCFFbw7. Finally, using the state of the art cell imaging facility of Montpellier (http://www.mri.cnrs.fr), an important program of our team is to analyse, using in vivo interaction techniques such as FRET (Fluorescence Resonance Energy Transfer) or FLIM (Fluorescence Lifetime Imaging Microscopy) where in the cell and when during cell cycle the 20S proteasome interacts with its regulators.
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Biard-Piechaczyk M., Borel S., Espert L., de Bettignies G. and Coux O. (2012). HIV-1, ubiquitin and ubiquitin-like proteins: the dialectic interactions of a virus with a sophisticated network of post-translational modifications. Biol. Cell 104: 165–187. http://www.ncbi.nlm.nih.gov/pubmed/22188301
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Thomas, Y., Coux, O., and Baldin, V. (2010). βTrCP-dependent degradation of CDC25B phosphatase at the metaphase-anaphase transition is a pre-requisite for correct mitotic exit. Cell Cycle 9, 4338–4350. http://www.ncbi.nlm.nih.gov/pubmed/21051950
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Linares, L. K., Kiernan, R., Triboulet, R., Chable-Bessia, C., Latreille, D., Cuvier, O., Lacroix, M., Le Cam, L., Coux, O., and Benkirane, M. (2007). Intrinsic ubiquitination activity of PCAF controls the stability of the oncoprotein Hdm2. Nat. Cell Biol 9, 331–338. http://www.ncbi.nlm.nih.gov/pubmed/17293853
Lassot, I., Latreille, D., Rousset, E., Sourisseau, M., Linares, L. K., Chable-Bessia, C., Coux, O., Benkirane, M., and Kiernan, R. E. (2007). The proteasome regulates HIV-1 transcription by both proteolytic and nonproteolytic mechanisms. Mol Cell 25, 369–383. http://www.ncbi.nlm.nih.gov/pubmed/17289585
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