The Peter Citation Classics

Previous Accomplishments

In recent years apoptosis has emerged as an fundamental process important in tissue homeostasis, the immune system (1) and during development. Countless diseases are characterized by dysregulation in apoptosis (2,3). The Peter laboratory has been studying apoptosis signaling pathways. About 120 dedicated apoptosis inducing or signaling proteins are known. The main focus has been the function of the members of the death effector domain (DED) proteins. The DED is a structural motif found in a number of apoptosis signaling proteins many of which couple to the apoptosis inducing death receptors (4-7). The best characterized member of this family of receptors is CD95 (APO-1/Fas) (4-6,8-15). Just like TNF-RI and four other members of this family, TRAMP/Wsl/APO-3R/DR3/AIR, APO-2R/TRAIL-R/DR4, DR5/TRICK2/TRAIL-R2, and DR6 CD95 carries an intracellular death domain (DD) by which it engages the apoptosis machinery.

From 1995-2005 The Peter lab either identified or cloned and characterized the following DED containing proteins:

• 1. FADD - Identified in a complex of signaling proteins they called the death-inducing signaling complex (DISC) that forms at the activated CD95 receptor (15-19). They also demonstrated that FADD is selectively phosphorylated at serine 194 by a cell cycle specific kinase (20,21) that was identified as casein kinase Ia (22).
• 2. Caspase-8 - Cloned as the main initiator caspase which is a part of the DISC and initiates the so called extrinsic apoptosis pathway (in collaboration with Matthias Mann and Vishva Dixit) (23,24).
• 3. v-FLIP - Cloned and characterized this inhibitor of the DISC in collaboration with Juerg Tschopp (25).
• 4. c-FLIP - Cloned this regulator of the activity of caspase-8 in the DISC. They showed in collaboration with Xiaolu Yang, that at low concentration c-FLIPL promotes activation of caspase-8 in the DISC (26) and at high concentrations it inhibits (27).
• 5. DEDD - Cloned this highly conserved factor that acts both in nucleoli (involved in transcriptional regulation, 28,29) and in the cytosol, where it facilitates cleavage of intermediate filament proteins by caspase-3 (30,31). DEDD is a platform protein that is critical for assembly of effector molecules in the apoptosis pathway. Its activity is regulated by monoubiquitination (30-33).
• 6. DEDD2 - Cloned this protein which is 48% identical to DEDD and acts together with DEDD on intermediate filaments (30).

Derived from these studies were a number of functional studies on pathways, their physiological roles in cells, tumors, organelles and their role in disease:

• 7. Caspase-8 is activated at the DISC (34) through interdimer cleavage (35).
• 8. One of caspase-8 main substrates is the cytolinker plectin (36).
• 9. Certain cells the Peter lab called Type I cells execute the CD95 apoptosis program independently of mitochondria whereas others (Type II cells) require mitochondrial amplification (37-39). Therefore only Type II cells are rendered CD95 apoptosis resistant by overexpression/upregulation of Bcl-2 or Bcl-xL. Another feature of Type II cells is that they do not efficiently form a DISC (1,37,39,40).
• 10. In apoptosis resistant peripheral T cells caspase-8 is not recruited to the DISC (27,41). Upon prolonged T cell activation these cells differentiated from a Bcl-xL protected Type II to a CD95 sensitive Type I phenotype (27).
• 11. Bcl-xL acts downstream, of the DISC but upstream of mitochondria (42).
• 12. Mitochondria of Bcl-xL protected cells the ability to sequester and inactivate active caspase-8 with the help of a mitochondrial protein BAR (43).
• 13. In a model of streptozotocin-induced autoimmune diabetes the Peter group found that pancreatic islets taken from CD95 mutant mice (lpr mice) were resistant to autoimmune destruction when transplanted under kidney capsule of autoimmune mice whereas islets from wild-type mice were destroyed demonstrating a proapoptotic role of CD95 in type I diabetes (44).

References

1.	Scaffidi, C., Kirchhoff, S., Krammer, P.H. and Peter, M.E. (1999) Apoptosis signaling in lymphocytes. Curr. Opin. Immunol., 11, 277-285.
2.	Peter,M.E., Heufelder, A. and Hengartner, M.O (1997) Advances in apoptosis research. Proc. Natl. Acad. Sci. USA, 94, 12736-12737.
3.	Peter,M.E., Ehret, A., Berndt., C. and Krammer, P.H. (1997) AIDS and the death receptors. British Medical Bulletin, 52, 604-616.
4.	Peter,M.E., Scaffidi, C., Medema, J.P., Kischkel, F. and Krammer, P.H. (1998) "The Death Receptors", in Apoptosis: Biology and Mechanisms (ed. Kumar S.), Results and problems in cell differentiation vol. 23, Springer-Verlag, Heidelberg, pp. 25-63.
5.	Schulze-Osthoff, K. Ferrari, D., Los, M., Wesselborg, S. and Peter, M.E. (1998) Apoptosis signaling by death receptors. Eur. J. Biochem., 254, 439-459.
6.	Peter,M.E. and Krammer, P.H. (1998) Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr. Opin. Immunol., 10, 545-551.
7.	Schulze-Osthoff, K. and Peter, M.E. (1999) The death receptors. In: Signaling pathways in Apoptosis. (Eds. M. Lavin, D. Watters); Series: Modern Genetics Vol. 5, Harwood Academic Publishers. pp31-54.
8.	Krammer, P.H., Dhein, J., Walczak, H., Behrmann, I., Mariani, S., Matiba, B., Fath, M., Daniel, P.T., Knipping, E., Westendorp, M.O., Stricker, K., Bäumler, C., Hellbardt, S., Germer, M., Peter, M.E. and Debatin, K.-M. (1994) The role of APO-1-mediated apoptosis in the immune system. Immunol. Rev., 142, 175-191.
9.	Peter,M.E., Westendorp, M.O., Walczak, H., Hellbardt, S., Knipping, E. and Krammer, P.H. (1995) APO-1-mediated apoptosis in the immune system. Futura, The Journal of the Boehringer Ingelheim Fond, 10, 21-26.
10.	Peter,M.E. (1996) CD95-associating signaling molecules. in Symposium in Immunology VI: Tumor Immunology (Eds.: Eibl, Huber, Peter, Wahn), Springer, Heidelberg pp.49-56.
11.	Walczak, H., Dhein, J., Peter,M.E. und Krammer, P.H. (1996) Activation-induced T cell death. Cell Death Differ., 3, 345.
12.	Peter,M.E., Chinnayian, A., Hellbardt, S., Kischkel, F., Krammer, P.H. and Dixit, V.M. (1996) The CD95 (APO-1/Fas) associating signaling molecules. Cell Death Differ., 3, 161-170.
13.	Peter,M.E., Ehret, A., Berndt., C. and Krammer, P.H. (1997) AIDS and the death receptors. British Medical Bulletin, 52, 604-616.
14.	Peter,M.E., Barnhart, B.C. and Algeciras-Schimnich, A. (2003) FasL/CD95L and its receptor CD95 (APO-1/Fas). in "Cytokine Handbook", 4th Edition. Ed. A. Thomson, M. Lotze. Academic Press. Vol.2, pp. 885-911.
15.	Peter,M.E. and Krammer, P.H. (2003) The CD95 death-inducing signaling complex and beyond. Cell Death Differ., 10, 26-35.
16.	Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H. and Peter, M.E. (1995) Cytotoxicity-dependent APO-1(Fas/CD95)-associated proteins form a death-inducing signalling complex (DISC) with the receptor. EMBO J., 14, 5579-5588. Minireview in Cell: Ihle and Cleveland. (1995) Contenders in FasL/TNF signaling. Cell 81:479.
17.	Chinnaiyan, A.M., Tepper, C., Lou, L., O'Rourke, K., Seldin, M.A., Kischkel, F., Hellbardt, S., Krammer, P. H., Peter, M.E. and Dixit, V M. (1996) FADD/MORT1 is a common mediator of Fas/APO-1- and tumor necrosis factor-induced apoptosis. J. Biol. Chem., 271, 4961-4965.
18.	Scaffidi, C., Kischkel, F.C, Krammer P.H. and Peter, M.E. (1999) Isolation and analysis of the CD95 (APO-1/Fas) death-inducing signaling complex (DISC). Methods, a companion to Methods in Enzymology, 17, 287-291.
19.	Scaffidi, C., Krammer, P.H. and Peter, M.E. (2000) Analysis of the CD95 (APO-1/Fas) death-inducing signaling complex (DISC) by high resolution IEF/SDS-PAGE 2D gels. Methods in Enzymol., 322, 363-373.
20.	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.
21.	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, (accelerated publication).
22.	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.
23.	Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O' Rourke, K., Shevchenko, A., Scaffidi, C., Zhang, M., Ni, J., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E.* and Dixit, V.M.* (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex (DISC), Cell, 85, 817-827. *shared senior authorship. Voted by "Science" to be one of the top 10 discoveries of 1996. 3rd most cited paper in 1997.
24.	Scaffidi, C., Medema, J.P., Krammer, P.H. and Peter, M.E. (1997) FLICE is predominantly expressed as two functionally active isoforms, caspase-8/a and caspase-8/b. J. Biol. Chem., 272, 26953-26958.
25.	Thome, M., Schneider, P., Hofmann, K., Burns, K., Mattmann, C., Bodmer, J.-L., Schröter, M., Neipel, F., Scaffidi, C., Krammer, P.H., Peter, M.E. and Tschopp, J. (1997) Viral FLICE-inhibitory proteins (FLIPS) prevent apoptosis induced by death receptors, Nature, 386, 517-521.
26.	Chang, D.W., Xing,, Z., Pan, Y., Algeciras-Schimnich, A., Barnhart, B.C.,Yaish-Ohad, S., Peter, M. E. and Yang, X. (2002) c-FLIPL is a dual function regulator for caspase-8 activation and CD95 (APO-1/Fas-mediated apoptosis. EMBO J., 21: 3704-3714.
27.	Scaffidi, C., Schmitz, I., Krammer, P.H. and Peter, M.E. (1999) Role of c-FLIP in modulation of CD95-induced apoptosis, J. Biol. Chem., 274, 1541-1548.
28.	Stegh, A.H., Schickling, O., Ehret, A., Scaffidi, C., Peterhänsel, C., Längst, G., Hoffmann, T., Grummt, I., Krammer, P.H. and Peter, M.E. (1998) DEDD, a novel death effector containing apoptosis-inducing protein targeted to nucleoli. EMBO J., 17, 5974-5986.
29.	Schickling, O., Stegh, A.H., Byrd, J. and Peter, M.E. (2001) Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription. Cell Death Differ., 8, 1157-1168.
30.	Lee, J.C., Schickling, O., Stegh, A.H., Oshima, R., Dingsdale, D., Cohen, G.M. and Peter, M.E. (2002) DEDD regulates degradation of intermediate filaments during apoptosis. J. Cell Biol., 158, 1051-1066. Highlighted in the same issue of JCB: "DEDD spells death to caspase substrates".
31.	Dinsdale D., Lee J.C., Dewson G., Cohen, G.M. and Peter M.E. (2004) Intermediate filaments control the intracellular distribution of caspases during apoptosis. Am. J. Pathol., 164, 395-407.
32.	Lee, J.C. and Peter, M.E. (2003) Regulation of apoptosis by ubiquitination. Immunol. Rev., 193, 39-47.
33.	Lee, K.-H., Feig, C., Tchikov, V., Schickel, R., Hallas, C., Schuetze, S., Peter, M.E.* and Chan, A.C.* (2006) The role of receptor internalization in CD95 signaling. EMBO J., 25, 1009-1023. * shared senior authorship.Highlighted in Nature Immunol. 7, 373 (2006) as "CD95 internalization".
34.	Medema, J.P., Scaffidi, C., Kischkel, F.C., Shevchenko, A., Mann, M., Krammer, P.H. and Peter, M.E. (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J., 16, 2794-2804.
35.	Chang, D.W., Xing, Z., Capacio, V, Peter, M.E. and Yang, X. (2003) Interdimer processing mechanism of procaspase-8 activation. EMBO J., 22, 4132-4142.
36.	Stegh, A.H., Herrmann, H., Lampel, S., Weisenberger, D., Andrä, K., Seper, M., Wiche, G., Krammer, P.H. and Peter, M.E. (2000) Identification of the cytolinker plectin as a major early in vivo substrate for caspase-8 during CD95 and TNF-receptor mediated apoptosis. Mol. Cell. Biol., 20, 5665-5679.
37.	Scaffidi, C., Fulda, S., Srinivasan, A., Li, Feng, Friesen, C., Tomasseli, K.J.., Debatin, K.-M., Krammer, P.H. and Peter, M.E. (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J., 17, 1675-1687. Highlighted in The Scientist as one of the hot papers of 1998: "Deconstructing Tumor Necrosis Factor". (2000) The Scientist 14:19.
38.	Scaffidi, C., Schmitz, I., Zha, J., Korsmeyer, S.J., Krammer, P.H., Peter, M.E. (1999) Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J. Biol. Chem., 274, 22532-22538.
39.	Barnhart B.C., Alappat, E., and Peter, M.E. (2003) The CD95 Type I/Type II model. Sem. Immunol. 15, 185-193.
40.	Algeciras-Schimnich, A., Pietras, E., Barnhart, B.C., Legembre, P., Vijayan, S., Holbeck, S.L. and Peter, M.E. (2003) Two CD95 tumor classes with different sensitivites to antitumor drugs. Proc. Natl. Acad. Sci. USA, 100, 11445-11450.
41.	Peter, M.E., Kischkel, F.C., Scheuerpflug, C., Medema, J.P., Debatin, K.-M. and Krammer, P.H. (1997). Resistance of cultured peripheral T cells towards activation induced cell death involves a lack of recruitment of FLICE to the death-inducing signaling complex (DISC). Eur. J. Immunol., 27, 1207-1212.
42.	Medema, J.P., Scaffidi, C., Krammer, P.H. and Peter, M.E. (1998) Bcl-xL acts downstream of caspase-8 activation by the death-inducing signaling complex, J. Biol. Chem., 273, 3388-3393.
43.	Stegh, A.H., Barnhart, B.C., Volkland, J, Algeciras-Schimnich, A, Ke N., Reed, J. and Peter,M.E. (2002) Inactivation of caspase-8 on mitochondria of Bcl-xL expressing MCF7-Fas cells: Role for the BAR protein. J. Biol. Chem., 277, 4351-4360.
44.	Vijayan, S., Zhou, P., Rajapaksha, T.W., Alegre, M.L. and Peter,M.E. (2005) Transplanted islets from lpr mice are resistant to autoimmune destruction in a model of streptozotocin-induced type I diabetes. Apoptosis, 10, 725-730. Highlighted in "Diabetes Week" 10/26/05.