Programmed cell death plays an important role during animal development, and defects in this process result in a variety of human disorders including cancer and autoimmunity. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. The regulation of apoptosis is relatively well understood, but little is known about the mechanisms that mediate autophagic programmed cell death. We are studying steroid-activated autophagic programmed cell death during development of the fruit fly Drosophila melanogaster using larval salivary gland cell death as a model. An increase in steroid titer triggers a genetic regulatory hierarchy that activates synchronous cell death in salivary glands. These cell deaths utilize apoptosis genes including caspase proteases, but salivary glands also possess the morphology of cells that die by autophagic cell death. We have used the combined strengths of Drosophila genetics and genomics to identify downstream targets of the cell death regulator E93 that appear to be involved in proteolysis during salivary gland autophagic cell death. Here we propose to: (1) identify E93 regulatory elements in new target genes and test if these elements are required for proper regulation during cell death, (2) investigate the function of the matrix metalloproteases in programmed cell death of salivary glands, and (3) determine the function of noncaspase protein degradation pathways (genes related to yeast apg/aut/cvt autophagy genes) in autophagic programmed cell death. The recent association of autophagic cell death with neurodegenerative disorders and cancer indicate the importance of investigating this understudied form of programmed cell death. ? ?
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