Genetic analysis of programmed cell death in Drosophila melanogaster

The correct regulation of programmed cell death, or apoptosis, is critical for proper development and prevention of disease. Components of the molecular mechanisms that govern apoptosis are conserved among organisms as diverse as C. elegans, Drosophila, and mammals. A central step in the execution of cell death is the activation of caspases, a conserved family of cysteine proteases. In Drosophila, the proteins, Reaper (Rpr), Head involution defective (Hid), and Grim, induce cell death via a mechanism that involves caspase activation. In order to further elucidate the mechanisms underlying the control of apoptosis, we conducted screens for genes involved in Rpr- or Hid-induced cell death. The analysis of the mutants isolated led to several new insights. The death inducing activity of Hid is post-transcriptionally down-regulated by the Ras/MAPK pathway. This is consistent with the pro-survival activity of this pathway and is probably mediated by direct phosphorylation of Hid. Furthermore, analysis of mutations in the gene encoding the Drosophila IAP, Diapl, led to a model for how Rpr, Hid and Grim activate caspases and induce cell death. In this model, Diapl binds and inhibits caspases; Rpr, Hid, and Grim induce cell death by binding Diapl and relieving caspases of Diapl-mediated inhibition. In addition, our mutants indicate that Diapl's RING finger domain, a domain found in proteins that function in ubiquitination, is required for inhibition of Rpr- and Grim-induced death but not Hid-induced death.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Agapite, Julie, 1968-

Advisor dc:contributor.advisor

• Hermann Steller.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/8321

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8321