Our research group focuses on the large field of “Redox Biology”, notably on iron-sulfur (Fe-S) proteins, redox signaling, and regulation of reactive oxygen and nitrogen species (ROS/RNS) production in non-pathological and pathological contexts, using molecular and cellular approaches, as well as different model organisms.
Functional studies of NEET Fe-S protein family in mammalian cells and molecular mechanisms of drugs targeting Fe-S proteins (Project leader: Marie-Pierre Golinelli).
Iron–sulfur proteins are proteins characterized by the presence of Fe-S clusters that are prosthetic groups composed of only iron and sulfur atoms. Well known to be involved in electron transfer in major cellular pathways, several Fe-S proteins were more recently shown to be involved in the sensing of oxidative/nitrosative stresses and in the regulation of cellular adaptive responses. Among them, NEET proteins are membrane-anchored Fe-S proteins able to potentially transfer their cluster to recipient proteins under the control of the redox state of the cluster. We have been interested in the mitochondrial NEET protein mitoNEET/CISD1, involving in iron homeostasis in response to oxidative/nitrosative stress, and the ER-anchored NEET protein CISD2. CISD2 mutations are associated with a rare genetic disorder, the Wolfram Syndrome type 2 and CISD2 is overexpressed in many human cancer types. These studies have been carried out combining complementary approaches from biophysics, biochemistry to cellular biology and involve a large network of collaborations. We are also focusing on drugs targeting Fe-S proteins as anti-malaria drugs involving ROS production and degradation of Fe-S proteins.
Molecular functions of the Dre2-Tah18 complex in yeast (Project leader: Laurence Vernis).
Budding yeast S. cerevisiae is an excellent model organism to study genetics, genomics and system biology. Yeast research has also paved the way to understand the molecular basis of many human diseases. Complementary to the functional studies of Fe-S proteins in mammalian cells in our group, we are particularly interested in the yeast Fe-S protein Dre2 that is involved in the biogenesis of the Fe-S clusters. Notably, Dre2 is the functional human counterpart of CIAPIN1, an antiapoptotic protein involved in many cancers. Dre2 has been the subject of extensive laboratory studies and many molecular tools have already been developed in our group. We identified that Dre2 forms a highly stable, cytosolic protein complex together with the diflavin reductase Tah18. This interaction is essential for cellular viability. We are currently performing studies to identify new partners of Dre2 that will help better understand the role of this essential protein in several cellular pathways, including cytosolic Fe-S biogenesis, iron homeostasis and oxidative stress response. A yeast cell drug screening assay based on the Dre2-Tah18 interaction is under development, in order to identity potential new antifungal or anticancer molecules.
Function of p73 in redox homeostasis and RNS/ROS production (Project leaders: Michel Lepoivre and Olivier Guittet).
The p73 gene is a member of the p53 family that is known to be involved in various physiological and pathological cellular processes. It encodes for transcriptionally active tumor suppressor TAp73 isoforms and oncogenic ∆Np73 isoforms that lack the N-terminal transactivation domain. It has been shown that TAp73 is involved in the cellular response to oxidative stress. In cancer. TAp73-dependent induction of a number of antioxidant enzymes help tumor cells to cope with a chronic mild oxidative stress resulting from reprogrammed metabolism. Much less is known regarding the interplay between p73 and reactive nitrogen species (RNS). We have recently identified a cooperation between TAp73 and the anti-inflammatory cytokine TGF-β in the suppression of nitric production induced in fibroblasts by pro-inflammatory cytokines. Future work will extend our investigations to the functions of ∆Np73 in inflammation, immunity and the adaptive response to oxidative and nitrosative stress in immune cells.
Oxidative stress- and redox-based anticancer therapeutic strategy (Project leader: Meng-Er Huang).
Many cancer cells produce elevated levels of reactive oxygen species and are under increased intrinsic oxidative stress. Different redox states in normal and malignant cells provide a therapeutic window for redox-mediated selective anticancer strategy. Our recent results support this concept. In particular, we have shown that auranofin, a US FDA-approved small-molecule used clinically to treat rheumatic arthritis, can kill breast cancer cells by increasing ROS production through inhibition of thioredoxin reductases and glutathione depletion. We are studying several auranofin-based drug combinations that display synergistic effect on breast cancer cells, leukemic cells, and lung cancer cells, in vitro (cellular models) and in vivo (mouse xenografts). A particular effort has been taken to better understand the mechanisms underlying cellular sensitivity/resistance to redox drugs. We are also interested in exploiting rational drug combinations for targeting both cancer redox alterations and metabolic reprogramming.
Our group is affiliated to:
- FrenchBIC, Groupe Français de Chimie Bio-Inorganique,
- the European COST Action CA15133 « The Biogenesis of Iron-Sulfur Proteins : from Cellular Biology to Molecular Aspects »,
- la Société Française de Biologie Cellulaire,
- la Société Française de Biochimie et Biologie Moléculaire.