Donald B. DeFranco, Ph.D.
Professor and Vice Chair, Pharmacology & Chemical Biology, Neuroscience- Ph.D. Yale University (1981)
- Office: 7041 Biomedical Science Tower 3
- Telephone:412-624-4259
- Fax:412-648-7029
- E-mail: dod1+@pitt.edu
- Website: http://www.pharmacology.us/Faculty.aspx?FacultyID=39
Signal transduction and neurodegeneration.
Research Summary:
A number of projects in Dr. DeFranco’s laboratory are focused on examining the molecular basis of neuronal cell death. His most recent work has revealed that aberrant signaling by a normal protective kinase module (i.e. extracellular signal regulated protein kinase-1/2; ERK-1/2) can in fact lead to detrimental effects on neuronal cell survival. The mechanisms responsible for ERK-1/2 dependent neuronal toxicity is the chronic activation and persistent nuclear retention of these kinases that is brought about by persistent inhibition of select protein phosphatases. The oxidative induced inhibition of specific protein phosphatases is not only driven by direct oxidation of redox sensitive cytosine thiols within these proteins, but also by the increased accumulation of Zn2+, which also directly inhibits their activity. Thus, the ERK-1/2 and Zn2+ signaling pathways are linked in neurons with protein phosphatases as the likely direct targets of damaging oxidants and divalent metal ions (i.e. Zn2+). Future work in this project utilizes both cell culture and primary neurons to uncover more mechanistic insights into the regulation of protein phosphatases by oxidant signaling and Zn2+ as well as validation of the physiological relevance of this signaling network utilizing rodent models of cerebral ischemia.
Dr. DeFranco’s laboratory is also interested in the action of glucocorticoid hormones in the brain. For this project they have focused on molecular analysis of the glucocorticoid receptor (GR) protein in hippocampal neurons. Recent studies suggest that specific E3 ubiquitin ligases (i.e. CHIP) may regulate GR function in developing neurons through an impact on receptor processing and downregulation. He is therefore interested in providing more detailed mechanistic insights into the manner in which GR is processed in developing neurons since a limitation in its downregulated in immature neurons may lead to prolonged or excess signaling particularly during a particularly vulnerable time during development of complex signaling networks in the forebrain.
Selected Publications:
Ho, Y., Samarasinghe, R., Knoch, M., Lewis, M., Aizenman, E. and DeFranco, D.B. Selective inhibition of MAPK phosphatases by zinc accounts for ERK1/2-dependent oxidative neuronal cell death. Mol. Pharm. 74, 1141-1151, 2008.
Ho, Y., Logue, E.S., Callaway, C.W. and DeFranco, D.B. Different mechanisms regulating ERK activation in distinct brain regions following global ischemia and reperfusion. Neuroscience, 145, 248-255, 2007
Wang, X. and DeFranco, D.B. Alternative effects of the ubiquitin-proteasome pathway on glucocorticoid receptor downregulation and transactivation are mediated by the CHIP E3 ligase. Mol. Endocrinol. 19, 1474-1482, 2005.
Witchell, S. and DeFranco, D.B. (2006) Mechanisms of Disease: regulation of glucocorticoid hormone and receptor levels-impact on the metabolic syndrome. Nature Clin. Pract. Endocrinol. Metabol. 2, 621-631, 2006.
Cummings, C.J., Mancini, M.A., Antalffy, B., DeFranco, D.B., Orr, H.T. and Zoghbi, H.Y. Chaperone suppression of ataxin-1 aggregation and altered subcellular proteosome localization imply misfolding in SCA1. Nature Genet. 19, 148-154, 1998.