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Activators of apoptosis
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 Drosophila caspase, referred to as Dredd. Dredd is
highly related to the nematode gene CED-3 and mammalian Caspase
8/ FLICE and at least one isoform is sufficient to elicit apoptosis.
Dredd is unique among the Drosophila caspases because of features
found in its long prodomain and a novel residue found at its active
site. Cell killing by the death activators Reaper, Grim
or Hid is suppressed by deletions of the Dredd locus. Furthermore,
these same apoptosis activators promote both activational processing
of Dredd protein and the accumulation of Dredd RNA in cells that
were specified to die. Together, these observations implicate
a novel mechanism that promotes "feed-forward" amplification
of caspase function during programmed cell death. Current
studies are focused toward understanding how the apoptotic activators
engage this and other caspases.
Control of caspase activation
Very recently we discovered an important regulator of caspase
activation in flies, referred to as Dark. This is a newly
identified Drosophila gene, homologous to both human Apaf-1 and
nematode CED-4. Like its mammalian counterpart, Dark evidently
constitutes a regulated "bridge" between mitochondrial
signals and the apical caspases. Mutations at Dark exhibit
profound failures in programmed cell death and, in related genetic
studies, we established that Dark is an important effector of
apoptosis signaling by Reaper, Grim and Hid. Current studies
are directed towards understanding how these activators promote
Dark-induced caspase activation. As part of this effort,
we are testing the role of two Drosophila bcl2 family members
as potential regulators in this process.
Damage-inducible apoptotic responses
One of the PCD-activators, Reaper, also contributes important functions during
"unscheduled" apoptosis provoked either by radiation or during aberrant
development. Using reporter transgenes, we established that the Reaper
promoter contains separate modular elements that are distinctly responsive to
cues that elicit unscheduled apoptosis. Transactivation of the Reaper
locus evidently functions as an integrating switch to specify cell death during
normal PCD and as an adaptive response to injury. Current efforts are
devoted to studies of radiation-induced determinants that engage this cell death
regulator.
Exploring
Noncanonical Genomic Transcription
New technologies in genomic sciences offer opportunities to explore the
informational content of genomes in ways never before possible. Over the last
few years, genome-wide expression analyses at the RNA level have become feasible,
if not routine. While these methods have vastly improved our analytical power,
the ‘junk DNA paradox’ is still unresolved. We remain largely ignorant
regarding vast portions of the genome that don’t encode protein protein
products and the extent of transcription though this ‘genomic dark matter’
is not known. By adapting existing methodologies, we are attempting to advance
the operational definition of gene activity and extract more complete informational
content from sequenced genomes. This objective can be achieved through systematic
and unbiased determinations of transcriptional activity at high resolution.
Toward this end, we have initiated a ‘saturation tiling’ approach,
capable of profiling all transcriptional activity (on both strands) spanning
more than half a megabase of chromosomal DNA. Transcribed sequences corresponding
to unpredicted, noncanonical activity are being tested for authentic biologic
function.
Akdemir,
F., Christich, A., Sogame, N., Chapo, J., and Abrams, J.M.
p53 Directs Focused Genomic Responses in Drosophila (2007). Oncogene
26: 5184-93
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.(2007)
J. Cell Biology 178:567-74
Akdemir, F., Farkas, R., Chen, P., Juhasz, G., Medvedova, L., Sass, M., Wang, L., Wang,X., Chittaranjan, S., Gorski,S.,M., Rodriguez, A., Abrams, J.M. Autophagy Occurs Upstream or Parrallel to the Apoptosome During Histolytic Cell Death. (2006) Development (133) 1457-1465
Chew, S., Akdemir, F.,Chen, P., Lu, W., Mills, K.,Daish, T.,Kumar, S., Rodriguez,, A. and Abrams, J.M. (2004). The Apical Caspase, dronc, Governs Programmed and Unprogrammed Cell Death in Drosophila. Developmental Cell (7): 897-907
Sogame, N., Kim, M. and Abrams, J.M. (2003) Drosophila p53 preserves genomic stability by regulating cell death. Proc. Natl Acad. Sci, USA 100 (8): 4696-4701
Abrams, J.M. (2002) Competition and Compensation: Coupled to Death in Development and Cancer. Cell 110, 403-406
Rodriguez, A., Oliver, H. and Abrams, J. M. (2002) Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog Dark. EMBO J 21(9): 2189-2197
Christich, A. Kauppila, S., Chen, P., Sogame, N., Ho, S., and Abrams, J. M. (2002) The damage- responsive Drosophila gene, sickle, encodes a novel IAP binding protein similar to, but distinct from, reaper, grim and hid. Current Biology 12: 137-140
Brodsky, M. H., Nordstrom, W., Tsang, G., Kwan, E., Rubin, G. M., and Abrams, J. M. (2000) Drosophila p53 binds a damage response element at the reaper locus. Cell 101: 103-113
Abrams, J. M. (1999) An emerging blueprint for apoptosis in Drosophila. Trends in Cell Biology 9: 435-440
Rodriguez, A., Oliver, H., Zou, H., Chen, P., Wang, X. and Abrams, J. M. (1999) Dark, is a Drosophila Homologue of Apaf-1/Ced-4 and Functions in an Evolutionarily Conserved Death Pathway. Nature Cell Biology 1: 272-279
Varkey, J., Chen, P., Jemmerson, R. and Abrams, J. M. (1999) Altered cytochrome c display precedes apoptosis in Drosophila. J Cell Biol 144: 701-710
Chen, P., Rodriguez, A., Erskine, R., Thach, T. and Abrams J. M. (1998) Dredd, a novel Drosophila caspase, is an effector of the apoptosis activators Reaper, Grim and Hid. Dev Biol 201: 202-216
Rodriguez, A., Chen, P., and Abrams, J. M. (1998) Molecular Prophets of Death in the Fly. Am J Hum Genet 62: 514-519
Chen, P., Lee, P., Otto, L, and Abrams, J. M. (1996) The apoptotic function of REAPER is distinct from signaling by the TNFR1 Death Domain. J Biol Chem 271: 25735-25737
Nordstrom, W., Chen, P., Steller, H. and Abrams, J. M. (1996) Activation of the reaper gene during ectopic cell killing in Drosophila. Dev Biol 180: 213-226
Chen, P., Nordstrom, W., Stuart, B. and Abrams, J. M. (1996) Grim, a novel cell death gene in Drosophila. Genes & Development 10: 1773-1782
