Analysis of molecular interactions between c-FLIP and initiator caspases in the DISC of death receptors

• Applicant: Professor Dr. Ingo Schmitz
• Subject Area: Immunology
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 63669446

Apoptosis is essential for the development of multicellular organisms as well as the immunesystem of vertebrates and its deregulation may be involved in various diseases. Majormediators of apoptosis are so-called death receptors whose signaling pathways are tightlyregulated. One important regulator in this context is the cellular FLICE-inhibitory protein (c-FLIP), which is expressed in three isoforms on the protein level, namely c-FLIPlong, c-FLIPshortand c-FLIPR. So far, previous research has mostly concentrated on c-FLIPlong, which serves adual function in apoptosis regulation and might exert both anti- and pro-apoptotic activities.The role of the two short isoforms, however, is poorly characterized so far. Since the functionof the c-FLIPR isoform in vivo is virtually unknown, we have generated a transgenic mousethat will enable us to determine the role of this novel c-FLIP isoform in apoptosis andimmunity. Moreover, the expression of c-FLIPR via the vav promoter allows us for the firsttime to investigate the functions of c-FLIP in hematopoietic cells other than T cells, includingdendritic cells and B cells. Recent studies have surprisingly revealed the involvementapoptosis regulators in several non-apoptotic functions, such as cell proliferation anddifferentiation. The aim of this proposal is to clarify whether or not c-FLIP serves nonapoptoticfunctions in addition to the inhibition of apoptosis. If so, we will investigate whichsignaling pathways mediate such non-apoptotic functions. In this context, we will analyzewhether the three splice variants of c-FLIP differentially affect non-apoptotic signaling usingisoform-specific RNA interference (RNAi). Our transgenic mouse model will allow us odetermine the role of c-FLIP in proliferation in vivo. Taken together, the proposedexperiments will lead to a better understanding of mechanisms leading to autoimmunity andcancer.

• DFG Programme: Research Grants