Regulation of Apoptosis by Bcl-xL and other factors

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Programmed cell death is essential for survival of multicellular organisms and is probably also required for survival of species of unicellular organisms such as yeast. In metazoans, this highly regulated process serves to eliminate select embryonic structures, to sculpt and maintain organ systems, to match the number of neurons to their target tissues, to regulate the size of hormone-dependent tissues, to destroy autoreactive thymocytes and to otherwise eliminate undesirable cells. Disruption or dysregulation of programmed cell death is a critical contributor to the insufficient cell death that occurs during tumorigenesis or the inappropriate cell death that occurs in a variety of neurodegenerative disorders and a wide range of other human diseases. A growing number of genes have been identified in diverse species that regulate the molecular pathways of programmed cell death. Bcl-xL is a member of the Bcl-2 protein family that is abundantly expressed in neurons of the brain, localizes to mitochondria and is a potent inhibitor of programmed cell death in mammals. Elevated levels of Bcl-xL expression have been implicated in a variety of cancers and other maladies. However, the molecular mechanisms by which Bcl-xL and other Bcl-2 family proteins regulate cell survival/death and possibly other essential processes are not known. Deletion of Bcl-xL in mice results in early embryonic lethality and there are no reliable Bcl-xL-knockout cells available for study. Therefore, we constructed a conditional Bcl-xL knockout mouse, providing a new important tool to study the function of endogenous Bcl-xL in the nervous system. These neurons will be used to study the function of Bcl-xL in regulating mitochondria! morphology, metabolism and synaptic activity. Interestingly, Bcl-xL can also alter yeast mitochondrial morphology, function and cell death, implying that the biochemical functions of Bcl-xL reflect highly conserved mechanisms. Therefore, we also propose to apply the genetic tools of yeast to study the biochemical functions of Bcl-xL. This strategy complements the work in mammalian neurons and provides insight that would be difficult to acquire if we limit our work to mammals.