Synergism between IFNß and TNFa: non-canonical functions of STAT2 and IRF9 transcription factors

点击翻译按钮获取中文摘要

Virtually all cell types secrete cytokines, key soluble mediators, to transmit signal of danger to activate an appropriate biological response. Cytokines act via cell surface receptors to elicit specific intracellular messages, known as signaling cascades, which ultimately transfer the message to the genome through the induction of a specific set genes to define an appropriate response. The molecular mechanisms that explain how a specific cytokine triggers a specific molecular pathway are the focus of numerous studies. Most studies aimed at describing the signaling cascades and biological outcome of cytokines are performed in simplified models using single cytokine stimulation. However, in a physiological situation it is highly unlikely that a cell is stimulated by one cytokine at a time as in a particular situation multiple cytokines are produced simultaneously. As a consequence, a cell rather responds to a cocktail of cytokines to foster an appropriate gene expression response. Our group is working to describe the signaling mechanisms that occurs when cells are stimulated with two cytokines, Interferon and TNF. Elevated levels of both cytokines are notably induced upon pathogen detection or in inflammatory conditions. Our work in progress strongly supports the existence of previously uncharacterized signaling cascades induced by the Interferon and TNF when used simultaneously. These novel signaling cascades are associated with the specific gene expression responses. The ultimate goal of this research program is to decipher the molecular mechanisms by which cells specifically respond in a coordinated fashion to IFN+TNF. In addition to providing key cell biology understanding of situations with elevated IFN+TNF, this research program will highlight novel paradigms that will translate to stimulation by other combination of cytokines. Biochemistry, molecular and cellular biology and bioinformatics analyses are required to solve the complexity and dynamics of the signaling cascades. We are in a privileged position to contribute significantly on a long-term basis to the discovery of these novel basics molecular mechanisms that control cell function. Undergraduate and graduate students participating to this program will gain a diversified training in biochemistry and molecular and cellular biology.