Kansas City, Mo. (Feb. 6, 2009) – – The Stowers Institute’s Du Lab has collaborated with the Institute’s Proteomics Center and Cytometry Facility to make significant strides in understanding the role of nuclear caspase-2, an enzyme involved in process of programmed cell death known as apoptosis.

     The work was published today in the journal Cell.

     Apoptosis in mammalian cells is mediated mainly by caspases - a family of enzymes thought of as “executioners” of apoptotic cell death. Caspase-2 is an initiator caspase that splits other protein substrates within the cell to trigger apoptosis. Unlike other caspases, a fraction of caspase-2 constitutively localizes to the cell nucleus. Until now, however, it has remained a mystery whether the nuclear caspase-2 contributes to apoptosis or to other processes in response to DNA damage.

     In their investigation of this question, the Du Lab and their collaborators took a biochemical approach and discovered a new caspase-2 activating protein complex in the cell nucleus, which they named DNA-PKcs-PIDDosome.

     “In this complex, DNA-PKcs represents the central molecule that binds to the PIDD protein and to caspase-2 to form a complex that remains latent unless or until the DNA is damaged,” said Mingan Shi, Ph.D., Senior Research Associate and lead author on the paper. “When that happens, DNA-PKcs phosphorylates and activates caspase-2 while PIDD promotes the kinase activity of DNA-PKcs.”

     The team also discovered that when activated in this way, caspase-2 maintains the DNA-damage checkpoint to block progression of the cell cycle through the division phase and also affects the repair of DNA breaks in the non-homologous end joining (NHEJ) pathway. This discovery may have potential therapeutic implications as it relates to the DNA-damage checkpoint and to DNA repair, processes that can be closely associated with the formation of tumors when they malfunction.

     “Until now, we knew very little about how caspase-2 functioned in the cell nucleus, but in this work we were able to establish the novel nuclear protein complex DNA-PKcs-PIDDosome and to highlight a new connection of caspase-2 to the DNA-damage response pathway,” said Chunying Du, Ph.D., Assistant Investigator and senior author on the publication. “This discovery provides insight into the complexity of DNA-damage-response regulation mediated by caspase-2, an enzyme long implicated in the execution of apoptosis. This work was the result of a successful collaborative effort between the Stowers Institute’s Proteomics and Cytometry support facilities together with Dr. David Chen and his team at the University of Texas Southwestern Medical Center at Dallas and with Dr. Andreas Villunger and his team at Innsbruck Medical University in Austria.”

     Additional contributing authors from the Stowers Institute include Carolyn Vivian, Lab Manager; Chumin Ge, Ph.D., Postdoctoral Research Associate; Shigeo Sato, Ph.D., Research Specialist I; Chieri Tomomori-Sato, Ph.D., Senior Research Associate; Ruihong Zhu, Research Technician III; Jeffrey Haug, Managing Director - Cytometry Facility; Selene Swanson, Research Specialist II; Michael Washburn, Ph.D., Director of Proteomics; and Laurence Florens, Ph.D., Managing Director of Proteomics.

     Additional contributing authors from the University of Texas Southwestern Medical Center at Dallas include Kyung-Jong Lee, Ph.D.; Keiko Morotomi-Yano; and Benjamin Chen, Ph.D. Additional contributing authors from Innsbruck Medical University include Claudia Manzl, Ph.D.; and Florian Bock.

     In addition to her appointment at the Stowers Institute, Dr. Du holds an academic appointment as an Assistant Professor in the Department of Biochemistry & Molecular Biology at The University of Kansas School of Medicine. Learn more about her work at www.stowers.org/labs/DuLab.asp.

About the Stowers Institute for Medical Research
     Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing, treating, and curing disease. Jim and Virginia Stowers endowed the Institute with gifts totaling $2 billion. The endowment resides in a large cash reserve and in substantial ownership of American Century Investments, a privately held mutual fund company that represents exceptional value for the Institute’s future.