• Gadd45 proteins in immunity.

      Schmitz, Ingo; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2013)
      The vertebrate immune system protects the host against invading pathogens such as viruses, bacteria and parasites. It consists of an innate branch and an adaptive branch that provide immediate and long-lasting protection, respectively. As the immune system is composed of different cell types and distributed throughout the whole body, immune cells need to communicate with each other. Intercellular communication in the immune system is mediated by cytokines, which bind to specific receptors on the cell surface and activate intracellular signalling networks. Growth arrest and DNA damage-inducible 45 (Gadd45) proteins are important components of these intracellular signalling networks. They are induced by a number of cytokines and by bacterial lipopolysaccharide. Within the innate immune system, Gadd45 proteins are crucial for the differentiation of myeloid cells as well as for the function of granulocytes and macrophages. Moreover, Gadd45β regulates autophagy, a catabolic pathway that also degrades intracellular pathogens. Regarding adaptive immunity, Gadd45 proteins are especially well characterized in T cells. For instance, Gadd45β and Gadd45γ regulate cytokine expression and Th1 differentiation, while Gadd45α inhibits p38 kinase activation downstream of the T cell receptor. Due to their many functions in the immune system, deficiency in Gadd45 proteins causes autoimmune diseases and less efficient tumour immunosurveillance.
    • The role of c-FLIP splice variants in urothelial tumours.

      Ewald, F; Ueffing, N; Brockmann, L; Hader, C; Telieps, T; Schuster, M; Schulz, W A; Schmitz, I; Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg and Department of Immune Control, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany. (2011)
      Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIP(long) (c-FLIP(L)) and c-FLIP(short) (c-FLIP(S)), which can have opposing functions. We observed diminished expression of the c-FLIP(L) isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIP(S) was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIP(L) to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours.