My lab explores two biomedical themes. One series of projects probes molecular networks that regulate cell death in vivo through exploration and discovery of relevant genetic determinants. A second organizing theme is designed to advance general principles underlying noncanonical transcription and noncoding RNAs.
CELL DEATH Our research examines gene-directed programs that specify programmed and unprogrammed cell death. In both vertebrates and invertebrates, dying cells often progress through a series of ultrastructural changes referred to as apoptosis. Stimuli that provoke apoptosis have been extensively investigated in numerous experimental models and it is well established that this form of programmed cell death requires conserved genetic functions within the dying cell. Apoptosis is important not only for development but also as an adaptive response during cellular injury and in viral infection. Consistent with this, extensive evidence links aberrant apoptosis to the etiology of cancer, neurodegenerative disorders, auto-immunities, AIDS and heart disease. Despite our well-advanced knowledge base, fundamental gaps in our understanding of apoptotic death in biology and medicine remain. A mounting body of literature supports the view that other forms of cell suicide also occur and, like apoptosis, these alternate forms of cell death are also controlled through genetically encoded programs.
PREVIOUS RESEARCH We exploit a genetic model, Drosophila, to understand the physiology of cell death during normal development and after cell injury. In this animal, deletion of a complex genomic interval, designated the Reaper region, prevents all programmed cell death (PCD). We discovered four genes in this region (Reaper, Grim, Hid and Sickle) that function as potent activators of the apoptotic pathway. Proteins encoded by the Reaper region function, in part, to liberate active caspases from inhibition by IAPs (Inhibitor of apoptosis proteins) through activities that are homologous to mammalian IAP antagonists (e.g. Smac/Diablo). In previous work, we also discovered another essential regulator of apical caspase activation in flies, referred to as Dark. This gene is homologous to both human Apaf-1 and nematode CED-4. Like its mammalian counterpart, the protein is essential for the apoptogenic action of apical caspases and mutations at this gene exhibit profound failures in apoptosis. In related studies, we also established that Dark is a central effector of histolytic cell death and pivotal in some models of pathologic injury, where cell death is provoked by genotoxic stress or polyglutamine toxicity. In previous work, our lab also are conducted genetic analyses of the two apical caspases in flies, Dronc and Dredd. The former, Dronc, encodes the only CARD containing caspase in the Drosophila genome and, as such, exhibits shared structural features with initiator caspases in mammals. Animals lacking Dronc present a range of defects, including extensive hyperplasia of hematopoietic tissues and persisting neuronal cells and, in ex vivo preparations, Dronc- cells were completely insensitive to induction of cell killing by diverse stimuli. Together, these studies place Dronc, and its activator Dark, at an obligate position for diverse pathways that specify PCD and stress-induced apoptosis.
COMMUNAL CELL DEATH We developed live reporter systems for real time imaging of cell death in vivo. Combining these tools and methods, we discovered a form of collective cell death, where synchronous apoptosis is coordinated throughout the tissue, causing wholesale loss of an entire epithelium within minutes (Movies can be viewed at: http://www4.utsouthwestern.edu/abramslab/research.htm). This communal behavior starkly contrasts with typical apoptosis models in developing systems, where a single cell, surrounded by viable neighbors, sporadically initiates apoptosis. Current studies are examining how this collective form of cell death is coordinated to affect dramatic change as part of tissue remodeling.
NEW CELL DEATH GENES Like mammalian counterparts, the Drosophila apoptosome, occupies a central position in networks that specify PCD. To advance a comprehensive view of pivotal cell death regulators and discover novel apoptogenic functions, we adopt biased and unbiased approaches. Current unbiased strategies include forward genetic screens and high throughput gene silencing platforms.
THE Dp53 REGULATORY NETWORK The p53 tumor suppressor preserves genomic stability and constrains oncogenic potential through activities that govern adaptive responses to genotoxic stress. This gene is perhaps the most highly studied in all of biomedical research. We have an incredibly rich body of knowledge about the function of p53 at the single cell level but very little is known about how this gene might function among cell groups to elicit adaptive responses at the tissue level. To illuminate core ancestral functions of this critical tumor suppressor and understand how this gene coordinates injury responses at the tissue level, we initiated a comprehensive analysis of the sole p53 family member encoded in the Drosophila genome, Dp53. Like its counterpart in mammalian systems, Dp53 is a crucial determinant of genome stability and is also essential for stress-induced apoptotic responses. Our broad goal is to explore conserved properties of adaptive stress responses as they engage the p53 regulatory network. We identified a signature profile for p53 dependent stress responses and established a novel method to examine the pro-apoptotic action of p53 in living animals. Together with real-time imaging methods, these tools permit us to examine p53 driven behaviors of living cells in situ. Because surrounding tissue fundamentally influences cell behavior, a strength of our approach comes from directed exploration of molecular circuits within a whole animal model. Current projects follow stimulus-dependent p53 action in live tissues to discover new determinants that specify adaptive responses beyond the single cell level.
NONCANONICAL TRANSCRIPTION New technologies in genomic sciences offer opportunities to explore the content of genomes in ways never before possible. While these advances have greatly improved our analytical power, we remain largely ignorant regarding vast portions of the genome that don?t encode protein products. The extent of unannotated ?non-coding? transcription is not accurately known but the significant (and possibly immense) levels of activity already detected raise new questions that challenge concepts of genetic information and influence perceptions of the junk DNA paradox. An important challenge that now confronts genome researchers is to find ways that move beyond descriptive studies of ?genomic dark matter? and determine how noncanonical RNAs might encode meaningful content. We believe it is possible to extract more complete informational content from sequenced genomes and advance the operational definition of genetic meaning. We are advancing this objective through unbiased determinations of transcriptional activity at high resolution, combined with innovative functional tests available in sophisticated model systems. Toward this goal, we conducted a pilot study that applies saturation tiling for unbiased mapping of stress-responsive noncanonical transcripts from a defined interval of the Drosophila genome. This analysis produced an exciting glimpse at a potentially vast dimension of under-appreciated transcriptional activity. To determine whether non-canonical RNAs encode authentic biologic function, we are interrogating unannotated transcripts for relevant phenotypes.
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
Chew, S.,Chen, P., Link, N., Galindo, K., Pogue, K. and Abrams, J.M., "Genome-Wide Silencing Captures Obligate Apoptotic Components in Drosophila" Nature, 460:123-7, July 2009
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
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
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., 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 Biol, 4 (178):567-74, August 2007
Chew, S.,Chen, P., Link, N., Galindo, K., Pogue, K. and Abrams, J.M., "Genome-Wide Silencing Captures Obligate Apoptotic Components in Drosophila" Nature, 460:123-127, July 2009
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