Cellular and molecular events in neural apoptosis and polyglutamine repeat expansion neurodegenerative diseases.
Cellular and molecular events regulating apoptosis and cellular pathology in polyglutamine neurodegenerative diseases
Cellular and molecular approaches are used to study signaling pathways controlling cell survival, cell death (apoptosis), and early nuclear events in polyglutamine neurodegenerative diseases. The two major projects in the lab are: 1) characterizing signaling pathways in the execution phase of apoptosis, and 2) investigating the relationship between CAG trinucleotide repeat proteins, the nuclear environment, the ubiquitin/proteasome machinery, and neuronal dysfunction/death. Apoptosis experiments are focused on understanding cellular events controlling signal transduction in the execution phase with particular emphasis on cytoskeletal changes associated with entry into the execution phase and dynamic membrane blebbing. Other studies on apoptosis are focused on kinase signaling at the interface of cell survival and cell death. Studies on the polyglutamine disease protein, ataxin-3, are currently focused on the relationship between the nuclear environment, transcriptional regulation, ubiquitination and proteasome system and neuronal dysfunction/death using cellular and animal models and reconstituted cellular and biochemical systems.
Zhong X and Pittman RN: Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates Hum Mol Genet 15: 2409-2420, 2006.
Bilen J, Liu N, Burnett BG, Pittman RN, Bonini NM: MicroRNA pathways modulate polyglutamine-induced neurodegeneration. Molecular Cell 24: 157-163, 2006.
Orlando KA, Stone NL, Pittman RN: Rho kinase regulates fragmentation and phagocytosis of apoptotic cells. Exper Cell Res 312: 5-15, 2006.
Burnett BG and Pittman RN: The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci USA 102: 4330-4335, 2005.
Burnett B, Li F, Pittman RN: The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12: 3195-3205, 2003.
Li F, Macfarlan T, Pittman* RN, Chakravarti* D: Ataxin-3 is a histone binding protein with two independent transcriptional corepressor activities. J Biol Chem 277: 45004-45012, 2002 Notes: *Co-communicating authors.
Zhou H, Li XM, Meinkoth J, Pittman RN: Akt regulates cell survival and apoptosis at a postmitochondrial level. J Cell Biol 151: 483-494, 2000.
Tang Y, Zhou H, Chen A, Pittman RN, Field J: The Akt proto-oncogene links Ras to Pak and cell survival signals. J Biol Chem 275: 9106-9109, 2000.
Perez MK, Paulson HL, Pittman RN: Ataxin-3 with an altered conformation that exposes the polyglutamine domain is associated with the nuclear matrix. Hum Mol Genet 8: 2377-2385, 1999.
Mills JC, Stone NL, Pittman RN: Extranuclear apoptosis. The role of the cytoplasm in the execution phase. J Cell Biol 146: 703-708, 1999.
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Last updated: 07/07/2008
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