|For this article, Jennifer Fisher Wilson interviewed Marcus E. Peter, an associate professor at the Ben May Institute for Cancer Research, University of Chicago. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. |
C. Scaffidi, S. Fulda, A. Srinivasan, C. Friesen, F. Li, K.J. Tomaselli, K.M. Debatin, P.H. Krammer, and M.E. Peter, "Two CD95 (APO-1/Fas) signaling pathways," EMBO Journal, 17:1675-87, March 16, 1998. (Cited in more than 210 papers since publication)
Tumor necrosis factor (TNF) has long been known to scientists as the key player in regulating cell proliferation and death. But only recently have scientists begun to understand how TNF and its related family members, the death ligands, function.
Diseases including cancer and AIDS are now known to be characterized by dysregulated apoptosis involving a subgroup of TNF receptors called the death receptors. Death receptors, distinguished by a death domain in their cytoplasmic region, trigger apoptosis when their cognate ligands or specific agonistic antibodies bind to the cells.
Marcus Peter, an associate professor at the Ben May Institute for Cancer Research, University of Chicago, has focused his research on CD95 (APO-1/Fas), the best-characterized member of the death receptor family.
"Our aim is to unravel the signaling pathways of these receptors to be able to positively or negatively modulate apoptosis sensitivity in these diseases," explains Peter. His current work at the University of Chicago is a continuation of research done at the German Cancer Research Center from 1992 to 1999 as the head of the "signaling group" in coauthor Peter Krammer's department.
Among other advances from this line of research, he and his group solved the perplexing question of the role of mitochondria in CD95-mediated apoptosis. "There were a number of contradicting data in the literature as to the involvement of mitochondria in CD95-mediated apoptosis," Peter says. To address this problem, he decided to directly compare cells that had been shown to be either independent of or dependent on mitochondria during CD95-mediated apoptosis. This was a "very obvious" approach that, all the same, had not yet been explored.
By directly comparing cells, he and his group found that there was a reason for the contradicting data. Their research identified two different cell types that use two different CD95 signaling pathways--one reliant on mitochondria and the other independent of mitochondria. "The results were black and white. We discovered these two CD95 apoptosis cell types," he said. The findings in this paper have advanced scientists' understanding of cell death. And the findings have a number of applications. In particular, the knowledge is now being used to design better tumor therapy.
In short, they found that the amount of active caspase-8 generated at the death-inducing signaling complex (DISC) in the presence of caspase-3 determines whether a mitochondria-independent CD95 signaling pathway is used (type I cells) or not used (type II cells).
Marcus Peter, far right, and lab members, from left, Alexander Stegh, Bryan Barnhart, Joerg Volkland, Nan Du, Olaf Schickling
Peter and his laboratory continue to explore CD95 functioning. They have found a possible reason that cells use different pathways. "We have found that the CD95 receptor on these two cell types has a different structure," he says. Because of the different receptor structure, requirements to stimulate CD95 on these cells may be different. He suggests that the different receptor for CD95 may be an adaptation of certain tissues to either the amount or the form (soluble or membrane bound) of CD95 ligand that the tissues encounter in their environment.
"We are working on all levels of the pathway. We continue to study the two CD95 signaling pathways, especially their role in peripheral T cells, since they seem to differentiate from one cell type to another during activation," Peter says. S
Jennifer Fisher Wilson is a freelance writer in Philadelphia.