Activators of apoptosis in Drosophila. -- The major focus of my research program exploits a genetic model, Drosophila, to understand how apoptotic physiology is regulated during normal development and after cell injury. In this animal, deletion of a complex genomic interval prevents all programmed cell death (PCD). Three genes mapping to this region (Reaper, Grim and Hid) function as potent activators of the apoptotic pathway. In germ line transformation experiments each locus partially "rescues" the cell death defective mutation and, in development, these death activators are expressed in patterns that precede the onset of PCD. In cultured cells and in transgenic animals, each gene is sufficient to provoke apoptosis that can be suppressed by caspase inhibitors. Reaper, Grim and Hid are therefore pivotal apoptosis activators that function through parallel circuits to engage a common set of effectors including caspases.
Caspase function. -- In efforts directed towards understanding the mechanisms through which these death activators exert their function, we identified a new apical caspase referred to as Dredd. Dredd is unique among the Drosophila caspases because it functions in both cell death and the innate immune response. Current studies are focused toward understanding how the apoptotic activators engage this and other caspases. As part of this effort we discovered an essential regulator of caspase activation referred to as Dark. This gene is homologous to both human Apaf-1 and nematode CED-4. Dark is an important effector of apoptosis signaling and, like its mammalian counterpart, this gene constitutes a regulated "bridge" between mitochondrial signals and the apical caspases, Dredd and Dronc. Current studies are directed towards understanding how death activators promote Dark-induced caspase activation. As part of this effort, we are examining the functions of Drosophila bcl2 family members.
Damage-inducible Cell Death. -- We recently characterized a Drosophila homolog of the tumor suppressor gene p53 (this gene is mutated in more50% of human tumors). Like its vertebrate counterpart, Drosophila p53 directs apoptotic cell death as an adaptive response to injury. This function is mediated, in part, by transactivation of the reaper gene. Current efforts are devoted to continuing studies of Drosophila p53 and other determinants that specify cell death in the context of genotoxic stress.
RESEARCH INTERESTS
Cell death; Apoptosis
Noncoding RNAs
Cancer; Radiation Biology
RECENT PUBLICATIONS
Chew, S., Akdemir, F.,Chen, P., Lu, W., Mills, K.,Daish, T.,Kumar, S.,Rodriguez,, A. and Abrams, J.M, "The Apical Caspase, dronc, Governs Programmed and Unprogrammed Cell Death in Drosophila" Developmental Cell, Volume 7:897-907, December 2004
Sogame, N., Kim, M. and Abrams, J.M., "Drosophila p53 preserves genomic stability by regulating cell death" Proc Natl Acad Sci U S A, 8 (100):4696-701, April 2003
Abrams, J. M., "Competition and Compensation: Coupled to Death in Development and Cancer" Cell, 110:403-406, 2002
Rodriguez, A., Oliver, H. , and Abrams, J.M., "Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog, Dark" EMBO J, 21 (9):2189-2197, 2002
Rodriguez, A., Oliver, H., Zou, H., Chen, P., Wang, X. and Abrams, J.M., "Dark, is a Drosophila Homologue of Apaf-1/Ced-4 and Functions in an Evolutionary Conserved Death Pathway." Nature Cell Biology, 1:272-279, 1999
SIGNIFICANT PUBLICATIONS
Brodsky, M, H. Nordstrom, W, Tsang, G., Kwan, E., Rubin, G.M. and Abrams, J.M., "Drosophila p53 binds a damage response element at the reaper locus" Cell, 101:103-113, 2000
Akdemir, F., Farkas, R., Chen, P., Juhasz, G., Medvedova, L., Sass, M., Wang, L., Wang, X., Chittaranian, S., Gorski, SM., Rodriguez, A., Abrams, JM, "Autophagy Occurs Upstream or Parallel to the Apoptosome During Histolytic Cell Death" Development, 133:1457-65, 2006
Akdemir, F., Christich, A., Sogame, N., Chapo, J., and Abrams, J.M, "p53 Directs Focused Genomic Responses in Drosophila" Oncogene, February 2007
Link, N., Chen, P., Lu, WJ, Pogue, K., Chuong, A., Mata, M., Checketts, J., Abrams, J.M, "A Collective Form of Cell Death Requires Homeodomain Interacting Protein Kinase" J. Cell Biology, in press August 2007
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