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FRISC: The Faculty Research Interests Science Comparator |
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Associate Professor of Cell Biology
Cell Regulation
Genetics and
Development
Office: (214) 648-9226
FAX: (214) 648-8694
Building K, Room 2.216
Email: john.abrams@utsouthwestern.edu
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 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 in Drosophila
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. As part of these studies, we recently characterized a Drosophila
homolog of the tumor suppressor gene p53 and found that, like its vertebrate counterpart,
Drosophila p53 is required for radiation-induced apoptosis. In related experiments, we
isolated a radiation-responsive enhancer upstream of reaper and established that
Drosophila p53 can directly bind this site. The studies indicate that reaper is a direct
target for Drosophila p53 in vivo .
Selected
Publications:
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 JM
(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 JM (1998) Molecular
Prophets of Death in the Fly. Am J Hum Genet 62:514-519
Chen P, Lee P, Otto L and Abrams JM (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 JM (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
Extraction Method: Expand using Medical Synonyms-
Eliminated words list: MedlinePlus List
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Similarity Method: Weighted keyword count
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Database: Medline abstracts (1967 - Present)
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Publication Type: All
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Score Calculation Method: Cosine Similarity Method
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Sort by: Score
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Show: Top 100 hits
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Results computed on: 6/9/2006