Abstract

By chance, the applicant has produced a truncated mutant of Bax, which turned out to be a potent suppressor of neuronal apoptosis. Much of his application will focus on this finding. He will begin by investigating the mechanism by which sympathetic neurons mature to a non-NGF dependent state; he proposes 3 hypotheses to test here: (a) loss of dependence is due to an alteration in pattern of expression of members of the BCL-2 family; (b) a protein is expressed that sequesters BAX in cytoplasm, thus preventing its translocation to the mitochondria; or (c) there is an age-dependent post-translational modification of BAX. The second specific aim is to extend structure-function analysis of truncation mutants of Bax as suppressors of neuronal apoptosis. He will also determine if truncation mutants of other pro-apoptotic members of the BCL-2 family are anti-apoptotic. His third specific aim is see if truncated BAX also protects other cell types, including macroglia, fibroblasts, and lymphocytes, against apoptosis.
Specific aim 4 will test whether truncated Bax blocks translocation of BAX to the mitochondria, or the loss of cytochrome c from the mitochondria. Finally, with an experienced collaborator, the investigator will generate tBAX transgenics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038651-05
Application #
6639571
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Gwinn, Katrina
Project Start
1999-05-10
Project End
2004-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
5
Fiscal Year
2003
Total Cost
$258,576
Indirect Cost

  Institution

Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Besirli, Cagri G; Johnson Jr, Eugene M (2006) The activation loop phosphorylation of protein kinase D is an early marker of neuronal DNA damage. J Neurochem 99:218-25
Wang, Leo H; Paden, Andrew J; Johnson Jr, Eugene M (2005) Mixed-lineage kinase inhibitors require the activation of Trk receptors to maintain long-term neuronal trophism and survival. J Pharmacol Exp Ther 312:1007-19
Besirli, Cagri G; Wagner, Erwin F; Johnson Jr, Eugene M (2005) The limited role of NH2-terminal c-Jun phosphorylation in neuronal apoptosis: identification of the nuclear pore complex as a potential target of the JNK pathway. J Cell Biol 170:401-11
Pierchala, Brian A; Ahrens, Rebecca C; Paden, Andrew J et al. (2004) Nerve growth factor promotes the survival of sympathetic neurons through the cooperative function of the protein kinase C and phosphatidylinositol 3-kinase pathways. J Biol Chem 279:27986-93
Putcha, G V; Johnson Jr, E M (2004) Men are but worms: neuronal cell death in C elegans and vertebrates. Cell Death Differ 11:38-48
Besirli, C G; Deckwerth, T L; Crowder, R J et al. (2003) Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons. Cell Death Differ 10:1045-58
Besirli, Cagri Giray; Johnson Jr, Eugene Malcolm (2003) JNK-independent activation of c-Jun during neuronal apoptosis induced by multiple DNA-damaging agents. J Biol Chem 278:22357-66
Putcha, Girish V; Le, Siyuan; Frank, Stephan et al. (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899-914
Chang, Louis K; Schmidt, Robert E; Johnson Jr, Eugene M (2003) Alternating metabolic pathways in NGF-deprived sympathetic neurons affect caspase-independent death. J Cell Biol 162:245-56
Chang, Louis K; Johnson Jr, Eugene M (2002) Cyclosporin A inhibits caspase-independent death of NGF-deprived sympathetic neurons: a potential role for mitochondrial permeability transition. J Cell Biol 157:771-81

Showing the most recent 10 out of 19 publications