2. The function of CD95 as a tumor promotor.

While the apoptosis inducing activity of CD95 may be important for eliminating certain tumor cells most cancer cells are completely resistant to CD95 induced apoptosis. However today not a single tumor has been reported that completely lacks CD95 expression. The Peter lab recently showed that on CD95 apoptosis resistant tumor cells and CD95 sensitive Type I tumor cells when treated with soluble CD95L stimulation of CD95 results in activation of NF-κB and MAP kinases inducing increased motility and invasiveness of tumor cells (1) (Figure). Two genes, urokinase plasminogen activator and the Ser/Thr kinase SNARK were identified to be critical for this activity of tumor cells (1,2). Recently it was found that the threshold for tumor cells to activate NF-κB is much lower than to activate apoptosis providing an explanation for the finding that patients with a mutation in one allele of the CD95 death domain (ALPS type Ia) have an increased risk of developing lymphoma (3). Activation of apoptosis in cells from these patients is blocked while activation of NF-κB and MAP kinases is normal. These findings underscore the novel role of death pathways and their components outside of apoptosis which are studied in the Peter lab (4-13). The lab is currently studying in vivo mouse tumor models in which CD95 acts as a tumor promotor with the goal to understand the nature and relevance of the tumor promoting activities of CD95. In one of these models it could recently been shown that a mutant CD95 receptor that does not allow apoptosis signaling to occur but still permits nonapoptotic signaling protects mice from developing liver cancer (14). The data support the view that nonapoptotic activities of the "death receptor" CD95 have been widely neglected (15).

References

1.	Barnhart, B.C., Legembre, P., Pietras, E., Bubici, C., Franzoso, G. and Peter, M.E. (2004) CD95 ligand induces motility and invasiveness of apoptosis resistant tumor cells. EMBO J., 23, 3175-3185. Press release by Nature Publishing Group on July 22, 2004, "Clue to Cancer spread". Article in New Scientist July 21, 2004, Vol. 183, 2458, "Renegade gene can aid and abet spread of cancer".
2.	Legembre, P., Schickel, R. Barnhart, B.C. and Peter, M.E. (2004) Identification of SNF1/AMPK-related kinase as a NF-κB regulated antiapoptotic kinase involved in CD95-induced motility and invasiveness. J. Biol. Chem., 279, 46742-46747.
3.	Legembre, P., Barnhart, B.C., Zheng, L., Vijayan, S., Straus, S.E., Puck, J., Dale, J.K., Lenardo, M. and Peter, M.E. (2004) Induction of apoptosis and activation of NF-kB by CD95 require different signaling thresholds. EMBO Reports, 5, 1084-1089.
4.	Barnhart, B.C. and Peter M.E. (2002) Two faces of caspase-8. Nature Immunol., 3: 896-898.
5.	Algeciras-Schimnich, A., Barnhart, B.C. and Peter, M.E. (2002) Apoptosis-independent functions of killer caspases. Curr. Opin. Cell Biol, 14, 721-726.1.
6.	Park, S.M., Schickel, R. and Peter, M.E. (2005) Nonapoptotic functions of death receptors and their signaling components. Curr. Opin. Cell Biol., 17, 610-616.
7.	Barnhart, B.C., Pietras, E., Algeciras-Schimnich, A., Salmena, L., Hakem, R. and Peter, M.E. (2005) Overcoming CD95 apoptosis resistance in certain cells through noncanonical activation of caspase-8. Cell Death Differ., 12, 25-37.
8.	Alappat, E.C., Feig, C., Boyerinas, B., Volkland, J., Samuels, M., Murmann, A.E., Thorburn, A., Kidd, V.J., Slaughter, C.A., Osborn, S., Winoto, A., Tang, W.-J. and Peter, M.E. (2005) Phosphorylation of FADD at serine 194 by CKIa regulates its nonapoptotic activities. Mol. Cell, 19, 321-332.
9.	Peter, M.E., Budd, R.C., Desbarats, J., Hedrick, S.M., Hueber, A.-O., Newell, M.K., Owen, L.B., Pope, R.M., Tschopp, J., Wajant, H., Wallach, D., Wiltrout, R.H., Zörnig, M. and Lynch, D.H. (2007) The CD95 receptor: Apoptosis revisited. Cell, 129, 447-450.
10.	Scaffidi, C., Volkland, J., Blomberg, I, Hoffmann, I., Krammer, P.H. and Peter, M.E. (2000) Phosphorylation of FADD/Mort1 at serine 194 and association with a 70 kDa cell cycle regulated kinase. J. Immunol., 164, 1236-1242.
11.	Alappat, E.C., Volkland, J. and Peter, M.E. (2003) Growth inhibition by C-FADD depends on its C-terminal phosphorylation site. J. Biol. Chem., 278, 41585-41588.
12.	Lee, JC, Barnhart, BC, Alappat, E. and Peter, M.E. (2003) The family of death effector proteins. Oncogene, 22, 8634-8644.
13.	Peter, M.E., Legembre, P., Barnhart, B.C. (2005) Does CD95 have tumor promoting activities? BBA - Reviews on Cancer, 1755, 25-36.
14.	Park, S.M., Rajapaksha, T.W., Zhang, M., Sattar, H.A., Fichera, A., Ashton-Rickardt, P.G., Peter, M.E. (2008) CD95 signaling deficient mice with a wild-type hematopoietic system are prone to hepatic neoplasia. Apoptosis, 13, 41-51.
15.	Peter, M.E., Budd, R.C., Desbarats, J., Hedrick, S.M., Hueber, A.-O., Newell, M.K., Owen, L.B., Pope, R.M., Tschopp, J., Wajant, H., Wallach, D., Wiltrout, R.H., Zörnig, M. and Lynch, D.H. (2007) The CD95 receptor: Apoptosis revisited. Cell, 129, 447-450.