Project Summary (from parent grant R35 GM118330) Genetic Control of Apoptosis and Apoptosis-induced Proliferation in Drosophila Principal Investigator: Andreas Bergmann, Ph.D. Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. Unexpectedly, evidence obtained in several organisms including Drosophila, Xenopus, Hydra, Mouse and human cancer suggests that regenerative AiP of amputated or otherwise damaged tissues including tumors depends on apoptotic caspases (highly specific cell death proteases) in a non-apoptotic function. The overall objective of this scientific program is to gain a comprehensive understanding of the biological principles that underlie the regulation of apoptosis and AiP in the context of a multi-cellular organism, to identify and characterize the genes involved in these processes, and to develop methods to manipulate them. We are using the genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by apoptosis. This cell death shares this developmental plasticity with vertebrates. Genetic screening for gene discovery and molecular genetic analysis in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis and AiP in vertebrates including humans. This program is also very relevant for understanding of human cancer. Our studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer, which may generate immortalized (undead) cells. Moreover, recent evidence has suggested that apoptotic tumor cells promote caspase-dependent AiP. For example, although radio- and chemotherapy attempt to cure cancer by killing tumor cells, relapse of treated tumors is frequently observed which may be due to an AiP-promoting activity of dying tumor cells. In summary, this program promises to improve our understanding of apoptosis and regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.