Investigating the essential roles of Ubiquitin-like molecules and the Ubiquitin Proteasome System
We interested at both better understanding cancer and improving its treatments.
More specifically, we are studying the involvement of various transcription factors in this disease, as those constitute essential molecular platforms for the integration of intra- and extracellular signals thorugh regulation of their activity by post-translational modifications such as phosphorylation, ubiquitylation and sumoylation.
In this context, we are addressing two complementary issues. First, we are investigating why and how two proteins related to the c-Fos proto-oncoprotein, Fra-1 and Fra-2, contribute to the metastatic phenotype in the breast tumors where they are overexpressed in hyperphosphorylated due to perverted cell signalling. This question is particularly important as metastatic breast cancer is the main cause of death by cancer amongst women. Secondly, we are studying how redox metabolism and transcription factor sumoylation, a post-transcriptional modification related to ubiquitin often altered in tumors, control the expression of transcriptomes and are involved in tumorigenesis and resistance to chemotherapies. To this aim, we are combining large-scale genomic and transcriptomic approaches to functional studies, both in vitro and in vivo in mouse models as well as using patient samples, with a special emphasis on leukemia with bad prognosis.
Keywords: breast cancer, leukemia, chemotherapy, Fos, Jun, AP-1, SUMO, ubiquitin/proteasome, cell signalling, transcriptome, large-scale genomic studies, redox metabolism
Figure 1. Protein of the Fos family accumulating in the nucleus (yellow), contrasting with a protein freely diffusing between the nucleus and the cytoplasm (red). Both intranuclear and intracellular distribution and dynamics of Fos and Jun proteins are regulated by phosphorylation, ubiquitylation and sumoylation.
Talotta F, Mega T, Bossis G, Casalino L, Basbous J, Jariel-Encontre I, Piechaczyk M, Verde P. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene. 2010 29(33):4732-4 http://www.ncbi.nlm.nih.gov/pubmed/20543861
Michaud HA, Gomard T, Gros L, Thiolon K, Nasser R, Jacquet C, Hernandez J, Piechaczyk M, Pelegrin M. A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy. PLoS Pathog. 2010 Jun 10;6(6):e1000948. http://www.ncbi.nlm.nih.gov/pubmed/20548955
Gomard T, Michaud HA, Tempé D, Thiolon K, Pelegrin M, Piechaczyk M. An NF-kappaB-dependent role for JunB in the induction of proinflammatory cytokines in LPS-activated bone marrow-derived dendritic cells. PLoS One. 2010 Mar 8;5(3):e9585. http://www.ncbi.nlm.nih.gov/pubmed/20548955
Malnou CE, Brockly F, Favard C, Moquet-Torcy G, Piechaczyk M, Jariel-Encontre I. Heterodimerization with different Jun proteins controls c-Fos intranuclear dynamics and distribution. J Biol Chem. 2010 285(9):6552-62. http://www.ncbi.nlm.nih.gov/pubmed/20053986
Jariel-Encontre I, Bossis G, Piechaczyk M. Ubiquitin-independent degradation of proteins by the proteasome. Biochim Biophys Acta. 2008 Dec;1786(2):153-77. http://www.ncbi.nlm.nih.gov/pubmed/18558098
Garaude J, Farrás R, Bossis G, Charni S, Piechaczyk M, Hipskind RA, Villalba M. SUMOylation regulates the transcriptional activity of JunB in T lymphocytes. J Immunol. 2008 180(9):5983-90. http://www.ncbi.nlm.nih.gov/pubmed/18424718
Baldin V, Militello M, Thomas Y, Doucet C, Fic W, Boireau S, Jariel-Encontre I, Piechaczyk M, Bertrand E, Tazi J, Coux O. A novel role for PA28gamma-proteasome in nuclear speckle organization and SR protein trafficking. Mol Biol Cell. 2008 19(4):1706-16. http://www.ncbi.nlm.nih.gov/pubmed/18256291
Malnou CE, Salem T, Brockly F, Wodrich H, Piechaczyk M, Jariel-Encontre I. Heterodimerization with Jun family members regulates c-Fos nucleocytoplasmic traffic. J Biol Chem. 2007 Oct 19;282(42):31046-59. http://www.ncbi.nlm.nih.gov/pubmed/17681951
Basbous J, Chalbos D, Hipskind R, Jariel-Encontre I, Piechaczyk M. Ubiquitin-independent proteasomal degradation of Fra-1 is antagonized by Erk1/2 pathway-mediated phosphorylation of a unique C-terminal destabilizer. Mol Cell Biol. 2007 27(11):3936-50. http://www.ncbi.nlm.nih.gov/pubmed/17371847
Functional connections between protein SUMOylation and reactive oxygen species.
Laboratory Web Page: www.igmm.cnrs.fr