Department of Pharmacology & Chemical Biology at the University of Pittsburgh
Donald B. DeFranco, PhD
Professor & Vice Chair of Medical Education, Associate Dean for Medical Student Research
7041 Biomedical Science Tower 3
3501 5th Ave, Pittsburgh, PA 15260

Email:
dod1@pitt.edu
Phone: 412-624-4259

Fax: 412-648-1945


Education

BA (Biology), Temple University, 1976. PhD (Molecular Biophysics and Biochemistry), Yale University, 1981. Postdoctoral Fellow, University of California, San Francisco, 1985.



Research Areas
Receptor Pharmacology
Neuropharmacology
Signal Transduction
Cancer Pharmacology
Pharmacology of Cell and Organ Systems
Photo of Donald B. DeFranco, PhD

Indirect immunofluorescent image of neurosphere derived from mouse embryonic cortex. Nuclei are stained blue (DAPI) and neural stem cell marker in red.


Indirect immunofluorescent image of neurosphere derived from mouse embryonic cortex. Nuclei are stained blue (DAPI) and neural stem cell marker in red.



Glucocorticoid hormones are widely used as prenatal agents for mothers at risk for preterm delivery and as postnatal agents in premature infants in order to decrease medical complications of prematurity. However, animal and clinical studies suggest that exposure of fetuses to glucocorticoids during development could affect future cognitive function and brain development. Delayed neurological effects of early glucocorticoid exposure may be mediated by reduced neural progenitor cell survival, proliferation or differentiation. We are using a number of in vivo and in vitro models to examine the role of the glucocorticoid receptor protein in survival and function of developing neurons in the cerebral cortex. Both genomic and nongenomic mechanisms of glucocorticoid receptor action are being studied to uncover both short and long term effects of these hormones.

 

 



Indirect immunofluorescent image of mouse embryonic cortex section. Nuclei are stained blue (DAPI), neural stem cell marker in green, and BrdU stained cells in red.
Indirect immunofluorescent image of mouse embryonic cortex section. Nuclei are stained blue (DAPI), neural stem cell marker in green, and BrdU stained cells in red.


 

Communication between the epithelial and stromal compartments of the prostate that is mediated by growth factors and cytokines is crucial for the maintenance of prostate growth and function. However, alterations in the expression and response to these factors can occur during prostate cancer progression and alter signaling between these compartments. We are examining various signaling pathways within the tumor microenvironment that mediate cross talk between cells within the stromal compartment and prostate cancer cells. For example, we have identified a prostate stromal cell specific transcriptional coactivator, the Hic-5 protein, that functions in both androgen and vitamin D signaling pathways. Hic-5 influences androgen regulation of paracrine factors in stromal cells. In addition, it is an important mediator of vitamin D response acting to regulate vitamin D metabolism in stromal cells and theantiproliferative response of this vitamin in prostate cancer cells.

 

Indirect immunofluorescent image of human prostate tissue section. Nuclei are stained blue (DAPI), smooth muscle alpha actin in red, and Hic-5 in green.

Indirect immunofluorescent image of human prostate tissue section.
Nuclei are stained blue (DAPI), smooth muscle alpha actin in red,
and Hic-5 in green.

 

We are also studying the TGF-beta signaling pathway with a particular interest in understanding the mechanism for its divergent action as both a tumor suppressor and tumor promoter. Recent studies revealed that human prostate cancer associated fibroblasts maintain a secreted activity that limits the migration of prostate cancer cells. However, TGF-beta derived from aggressive prostate cancer cells can block this migration inhibitory activity through activation of an ROS signaling pathway in the cancer-associated fibroblasts.

 

 

Training technologies used:

Neural stem cell cultures; mammalian cell culture; gene expression analysis; cell signaling assays

 





Important Publications
Ho Y, M Knoch, R Samarasinghe, E Aizenman and DB DeFranco. Selective inhibition of MAPK phosphatases by zinc accounts for ERK1/2-dependent oxidative neuronal cell death. Molecular Pharmacology 74:1141-1151, 2008.
Wolf IM, MD Heitzer, M Grubisha and DB DeFranco. Coactivators and nuclear receptor transactivation. J Cell Biochem 104:1580-1586, 2008.
Heitzer MD and DB DeFranco. Hic-5/ARA55 a LIM domain-containing nuclear receptor coactivator expressed in prostate stromal cells. Cancer Research 66: 7326-7333, 2006.
Witchell S and DB DeFranco. Mechanisms of disease: Regulation of glucocorticoid hormone and receptor levels-impact on the metabolic syndrome. Nature Clinical Practice: Endocrinology and Metabolism 2:621-631, 2006.
Levinthal DJ and DB DeFranco. Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. J Biol Chem 280:5875-5883, 2005.
Wang X and DB DeFranco. 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.
Elbi C, G Romero, D Walker, W Sullivan, DO Toft, GL Hager and DB DeFranco. Molecular chaperones function as nuclear mobility factors for steroid receptors. Proc Natl Acad Sci USA 101:2876-2881, 2004.
Jiang H, F Nucifora, CA Ross and DB DeFranco. Cell death triggered by polyglutamine-expanded huntinigtin in a neuronal cell line is associated with degradation of CREB-binding protein. Human Mol Genet 12:1-12, 2003.




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