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J. John Cohen MDCM, PhD

Professor of Immunology and Medicine
 
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Barbara Davis Center 4603B
Phone: 303-724-3998
E-mail: John.Cohen@UCDenver.edu

Our group has been working on apoptosis since 1980. Before that, we were trying to figure out why so many cells die in the thymus (about 98% of all thymocytes die, and only 2% mature). Also, we wanted to know how, because no matter how hard we looked, we could not find dead cells in thymus sections, although we knew that a third of the cells died each day. Where were the corpses? In 1980, Wyllie published an important paper saying that thymocytes die by apoptosis, and that morphology was accompanied by cleavage of their DNA into nucleosomes. This gave us a tool to study thymocyte death. We knew that glucocorticoids cause most thymocytes to die, and, like Wyllie, we repeated that in vitro, showing that the death was apoptotic. But steroids work (usually) by activating transcription: could death be a transcriptionally-activated (i.e., genetically-determined) event? This conclusion—at that time unthinkable, certainly to the editors of Nature—was quickly confirmed. We then asked: Is all cell death programmed? Karen Sellins looked at radiation-induced death of resting lymphocytes, and found that the radiation does not kill the cells; rather, it signals them to commit suicide. If you don’t allow protein systhesis, the cells don’t die. Rick Duke showed that killer cells (both cytotoxic T cells and NK cells) induce apoptosis in their targets. This finding caused consternation in granule exocytosis/perforin circles, where cytotoxicity had been considered a form of complement-like membrane attack, but the data with killer cells indicated otherwise. Eventually it was agreed that apoptosis takes place even in a perforin-depending killing event. Cathy McCall showed that the terminal differentiation of keratinocytes (skin cells) is by apoptosis. And Rick Duke was the first to show that cells become dependent on growth factors, and die by apoptosis when they are removed. We began a program to identify new genes expressed in apoptotic cells; Greg Owens isolated several by subtractive hybridization. Valerie Fadok, who was a graduate student in Peter Henson’s lab, made the important discovery that apoptotic cells "flip" phosphatidylserine to the outer leaflet of the plasma membrane; we are proud that we had a small part in that work. It led us to begin to consider the underlying biochemical events.

JJC coordinates the Department's teaching for all except Ph.D. graduate students. Courses include IMMU 6002 for second-year medical students, which can be taken by graduate and non-degree students as IMMU 7629 (Fall quarter). He also directs the immunology course for Child Health Associate Program students, using graduate students from the Immunology program to do the actual teaching. We also teach an on-line course for Pharm.D. students; this too is run by a group of graduate students spearheaded by Kara Lukin. Finally, in 2004 we took on the Dental immunology course; Lisa Lehman does all the work and JJ tries to take the credit.

We have a Web site with full text and excellent animations that goes with the medical immunology course. You can access it at: http://mama.uchsc.edu Click on IMMU 6002/7629, and log in as "immuno", pass word "tcell".

IMMU 7630: An Overview of Human Immunology

  • Cohen, J.J. and Claman, H.N. Thymus-marrow immunocompetence.V. Hydrocortisone-resistant cells and processes in the hemolytic antibody response of mice. 1971. J. Exp. Med. 133:1026-1034.
  • Cohen, J.J. and Duke, R.C. 1984. Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J. Immunol. 132:38-42.
  • Sellins, K.S. and Cohen, J.J. 1987. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J. Immunol. 139:3199-3206.
  • Duke R.C., Chervenak, R. and Cohen, J.J. 1983. Endogenous endonuclease-induced DNA fragmentation: an early event in cell-mediated cytolysis. Proc. Natl. Acad. Sci. USA 80:6361-6365.
  • Duke, R.C., Persechini, P.M., Chang, S., Liu,C.-C., Cohen, J.J., and Young, J.D. Purified perforin induces target cell lysis but not DNA fragmentation. J. Exp. Med. 170:14511456.
  • McCall, C.A. and Cohen, J.J. 1991. Programmed cell death in terminally differentiating keratinocytes: role of endogenous endonuclease. J. Invest. Dermatol. 97: 111-114.
  • Duke, R.C. and Cohen, J.J. 1986. IL-2 addiction: Withdrawal of growth factor activates a suicide program in dependent cells. Lymphokine Res. 5:289-300.
  • Owens, G.P., Hahn, W.E. and Cohen, J.J. 1991. Identification of mRNAs associated with programmed cell death in immature thymocytes. Mol. Cell. Biol. 11:4177-4188.
  • Fadok, V.A., Voelker, D.R., Campbell, P.A., Cohen, J.J., Bratton, D.L., and Henson, P.H. 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148:2207-2216.
  • Squier, M.K.T., Miller, A.C.K., Malkinson, A.M. and Cohen, J.J. 1994. Calpain activation in apoptosis. J. Cell. Physiol. 159:229-237.
  • Squier, M.K.T. and Cohen, J.J. 1997. Calpain: An upstream regulator of thymocyte apoptosis. J. Immunol. 158:3690-3697.
  • Squier, M.K.T., Sehnert, A.J., Sellins, K.S., Malkinson, A.M., Takano, E., and Cohen, J.J. 1999. Calpain and calpastatin regulate neutrophil apoptosis. J. Cell. Physiol. 178:311-319.
 

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