Education & Training
- Temple University, Philadelphia PA BA 05/1976 Biology
- Yale University, New Haven CT PhD 12/1981 Molecular Biophysics
- University of California, San Francisco CA Postdoc 05/1985 Biochemistry and Biophysics
A. Personal Statement
My laboratory has spent over 30 years examining glucocorticoid receptor function focusing predominantly on the mechanisms of glucocorticoid receptor transactivation, interaction with coactivators, subcellular and subnuclear trafficking, interactions with molecular chaperones and processing. We have also studied androgen receptor and estrogen receptor function with a particular emphasis on examining coregulators that impact androgen action in prostate and the regulation of estrogen receptor function by oxidative stress and TGFß signaling. For example, we identified a novel class of androgen receptor coregulators that are members of the Group III LIM domain family that includes the focal adhesion protein paxillin. Hic-5 is one such group III LIM domain protein highly related to paxillin that we have characterized as a stromal cell-selective androgen receptor and vitamin D receptor coregulator. We also identified a novel paracrine communication network between prostate epithelial and stromal cells that impacts estrogen receptor beta function, operating in part through a previously unidentified connection between cyclooxygenases and steroidogenesis. Our most recent work in the area of benign prostatic disorders has led to my participation (as a project leader) in an NIDDK funded O’Brien Center for Excellence in Benign Urology. In addition to productive collaborative research with members of the University of Pittsburgh’s O’Brien Center, we have been engaged in various collaborative efforts with the University of Wisconsin-Madison’s O’Brien Center particularly with the Center Director, Dr. William Ricke, and a K12 Scholar on his team, Dr. Teresa Liu, a former postdoc in my laboratory.
Representative publications (not listed in Section C) in the area of benign prostatic disorders with collaborators of relevance to this proposal highlighted in bold, italicized font.
1. Grubisha, MJ, Cifuentes ME, Hammes, S, DeFranco DB (2012) A local paracrine and endocrine network involving TGFβ, Cox-2, ROS and estrogen receptor beta impacts reactive stromal cell regulation of prostate cancer cell motility. Mol. Endocrinol 26, 940-954. PMCID: PMC3355541
2. Funahashi Y, O’Malley K, Kawamorita N, Tyagi O, DeFranco D, Takahashi R, Gotoh M, Wang Z, Yoshimura N (2014). Upregulation of androgen-responsive genes and transforming growth factor[1]ß1 cascade genes in a rat model of non-bacterial prostatic inflammation. Prostate 74, 337-345. PMCID: PMC3898594
3. Liu TT, Grubisha MJ, Frahm, KA, Wendell SG, Liu J, Ricke WA, Auchus RJ, DeFranco DB (2015). Opposing effects of cyclooxygenase-2 (COX-2) on estrogen receptor ß (ERß) response to 5α[1]reductase inhibition in prostate epithelial cells. J. Biol. Chem. 291, 14747-14760. PMCID: PMC4938192
4. Mizoguchi S, Mori K, Wang Z, Liu T, DeFranco DB, Yoshimura N & Mimata H (2017) Effects of estrogen receptor ß stimulation in a rat model of non-bacterial prostate inflammation. Prostate 77, 803-811. PMCID: PMC5968815
5. Li F, Pascal LE, Stolz DB, Wang K, Zhou Y, Chen W, Xu Y, Chen Y, Dhir R, Parwani AV, Nelson JB, DeFranco DB, Yoshimura N, Balasubramani GK, Gingrich JR, Maranchie JK, Jacobs BL, Davies BJ, Hrebinko RL, Bigley JD, McBride D, Guo P, He D, Wang Z (2019). E-cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer. Prostate 79, 1226-1237. PMCID: PMC6599563
B. Positions and Honors
Positions and Employment
1977-1981 Graduate Research Assistant, Laboratory of Dr. Dieter Söll, Department of
Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
1982-1985 Postdoctoral Fellow, Laboratory of Dr. Keith Yamamoto, Department of
Biochemistry and Biophysics, University of California, San Francisco, CA
1985-1991 Assistant Professor, Department of Biological Sciences, University of
Pittsburgh, Pittsburgh, PA
1991-1996 Associate Professor, Department of Biological Sciences, University of
Pittsburgh
1996-2000 Professor, Department of Biological Sciences, University of Pittsburgh
1997- Professor, Department of Neuroscience, University of Pittsburgh
(Secondary Appointment)
1998- Acting Chairman, Department of Biological Sciences, University of Pittsburgh
2000- Professor, Department of Pharmacology and Chemical Biology, University of
Pittsburgh School of Medicine (UPSOM)
2007- Vice Chair of Education, Department of Pharmacology and Chemical Biology,
UPSOM
2014- Associate Dean of Medical Student Research, UPSOM
Other Experience and Professional Memberships
1995-2008 Editorial Board (1995-2003), Associate Editor (2004-2008), Molecular
Endocrinology
1996-2001 Editorial Board, Journal of Biological Chemistry (1996-2001)
1997-2001 Editorial Board, Neuroendocrinology
2001-2003 Director, Molecular Biology Section of “Course in Neurobiology”, Marine
Biological Laboratory, Woods Hole, MA
2009–2014 Editor-in-Chief, Molecular Endocrinology
2014- Editorial Board, Nuclear Receptor Signaling
2020- Editor-in-Chief, Steroids
Honors
1976 Summa cum laude, Honors in Biology, Phi Beta Kappa, N.D. Lane Science
Prize
1982-1983 Damon Runyon-Walter Winchell Postdoctoral Fellowship
1986-1989 Basil O'Connor Starter Scholar Award, March of Dimes Foundation
1991-1996 Research Career Development Award, National Cancer Institute
2008 Provost’s Award for Excellence in Mentoring, University of Pittsburgh
2011 Sheldon Adler Award for Innovation in Medical Education, UPSOM
2015 Kenneth E Schuit Dean’s Award for Master Educator, UPSOM
Federal Government Public Advisory Committee Service
1992-1998 Endocrinology Study Section, ad-hoc (1992-1994), full member (1994-1998)
1993-2005 National Institutes of Health Special Emphasis Panels or Site Visits
1. NIDDK Program Project on "Mechanism of Growth Control by Steroids", UTHSC, Galveston, TX (11/93, 03/95)
2. NINDS Special Study Section, “Parkin Protein and Parkinson’s Disease” (11/00)
3. NINDS Special Mock Study Section on “Hypothermia and Neuroprotection”, University of Alaska-Fairbanks (09/02)
4. Biochemical and Endocrinology Sciences Study Section Special Emphasis Panel on “Reproductive Sciences” (03/03, 11/03)
5. NCI Program Project on “Mechanisms of Prostate Cancer”, University of Virginia (06/03, 02/04)
6. NIA Special Emphasis Panel on “Reproductive Hormones and the Brain” (11/05) 2007 Molecular and Cellular Endocrinology Study Section, ad-hoc member
2007-2013 Biomedical Research and Training (BRT-A)/ Training and Workforce
Development Subcommittee-A Study Section, full member
2014 Member, Board of Scientific Counselors, Review of Intramural Research
Program, NIEHS
2018 Full Member, Molecular and Cellular Endocrinology Study Section
C. Contrution to Science
Nucleocytoplasmic shuttling and trafficking of SRs: Our specific contributions to this area of steroid hormone action are highlighted by a 1991 Molecular Endocrinology publication (154 citations, Google Scholar) that identified for the first time specific protein phosphatases that act on GR and regulate its nucleocytoplasmic shuttling (1). Definitive proof of the nucleocytoplasmic shuttling of GR was provided in a 1993 landmark study (162 citations, Google Scholar) published in PNAS that characterized this unique trafficking pathway (2). In 1997 published a study in the influential Journal of Cell Biology that provided mechanistic insights into the subnuclear trafficking and nuclear export of GR (3). This was followed seven years later by a paper published in 2004 in PNAS that showed for the first time that molecular chaperones play a role in the subnuclear trafficking of GR (4).
1. DeFranco, D.B., Qi, M., Borror, K.B., Garabedian, M.J. and Brautigan, D.L. (1991). Protein phosphatase types 1 and/or 2A regulate nucleocytoplasmic shuttling of glucocorticoid receptors. Mol. Endocrinol. 5, 1215-1228. PMID: 1663212
2. Madan, A.P. and DeFranco, D.B. (1993). Bidirectional transport of glucocorticoid receptors across the nuclear envelope. Proc. Natl. Acad. Sci. USA 90, 3588-3592. PMCID: PMC46346
3. Yang, J., Liu, J. and DeFranco, D.B. (1997). Subnuclear trafficking of glucocorticoid receptors in vitro: chromatin recycling and nuclear export. J. Cell Biol. 137, 523-538. PMCID: PMC2139874
4. Elbi C, Romero G., Walker D., Sullivan W., Toft, D., Hager G.L., and DeFranco D.B. (2004). Molecular chaperones function as nuclear mobility factors for steroid receptors. Proc. Natl. Acad. Sci. USA, 101, 2876-2881. PMCID: PMC365713
Molecular Chaperones and Chromatin Dynamics: Our 1997 study published in Molecular Biology of the Cell was the first to definitively establish a role for a specific chaperone, the hsp40 family member HDJ-2, in alleviating misfolding and aggregation, as well as restore functionality, of a mutant transcription factor (GR) in the nucleus (5). In a landmark paper that resulted from a collaboration with Dr. Huda Zoghbi published in Nature Genetics (cover article), it was shown that HDJ-2 could suppress the aggregation of polyQ-expanded ataxin-1, the cause of spinocerebellar ataxia type 1 (6). This article (776 citations, Google Scholar) led the way to many studies (i.e. 383 publications in PubMed in search of “chaperone and poly-glutamine”) establishing a role for molecular chaperones in correcting the misfolding and/or aggregation of polyQ-expanded proteins and providing a therapeutic target for treatment for neurodegenerative diseases. A 2003 paper in collaboration with Dr. Christopher Ross based upon work largely performed by a graduate student in my laboratory (i.e. H. Jiang) published in Human Molecular Genetics uncovered a novel property of the polyQ-expanded huntingtin protein in triggering not only aggregation but degradation of the transcriptional coregulator CBP (7). Finally, we established for the first time the role of heat shock protein 90 in the dynamic recycling of GR from chromatin (8).
5. Tang, Y., Ramakrishnan, C., Thomas, J. and DeFranco, D.B. (1997). A role for HDJ2/HSDJ in correcting subnuclear trafficking, transactivation and transrepression of a glucocorticoid receptor zinc finger mutant. Mol. Biol. Cell 8, 795-809. PMCID: PMC276130
6. Cummings, C.J., Mancini, M.A., Antalffy, B., DeFranco, D.B., Orr, H.T., and Zoghbi, H.Y. (1998). Chaperone suppression of ataxin-1 aggregation and altered subcellular proteosome localization imply misfolding in SCA1. Nature Genet. 19, 148-154. PMID: 9620770
7. Jiang H, Nucifora, F., Ross, C.A., and DeFranco D.B. (2003). Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB- binding protein. Human Mol. Genet. 12, 1-12. PMID: 12490527
8. Liu, J. and DeFranco, D.B. (1999). Chromatin recycling of glucocorticoid receptors: Implications for multiple roles of heat shock protein 90. Mol. Endocrinol. 13, 355-365. PMID: 10076993
Neurodegenerative Role for ERK-1/2: Our work in the area of neurodegeneration, which was supported in part by an R01 grant from the National Institute of Neurodegenerative Diseases, resulted in 21 publications on topics relating to neurodegeneration using in vivo and in vitro models ranging from oxidative stress to cardiac arrest induced global cerebral ischemia. Our most influential work in this area is highlighted by the four publications cited below (9-12), which established the role the MAPK protein, extracellular signal regulated kinase-1/2 (ERK-1/2) in neurodegeneration. Prior to our landmark 2000 Journal of Biological Chemistry article (9) (436 citations, Google Scholar), the prevailing dogma had established a neuroprotective role for ERK-1/2. Our follow-up studies (10-12) went on to establish the mechanism for the neurotoxic effects of ERK-1/2.
9. Stanciu, M., Wang, Y., Kentor, R., Burke, N., Watkins, S., Kress, G., Reynolds, I., Klann, E., Angiolieri, M, Johnson, J., and DeFranco, D.B. (2000). Persistent activation of ERKs contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J. Biol. Chem. 275, 12200-12206. PMID: 10766856
10. Stanciu, M., and DeFranco, D.B. (2002). Prolonged nuclear retention of activated ERK promotes cell death generated by oxidative toxicity or proteasome inhibition in a neuronal cell line. J. Biol. Chem. 277, 4010-4017. PMID: 11726647
11. Levinthal DJ, DeFranco DB. (2005) Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons. J. Biol. Chem. 280, 5875-5883. PMID: 15579467
12. Ho Y, Samarasinghe R, Knoch ME, Lewis M, Aizenman E, DeFranco DB. (2008) Selective inhibition of MAPK phosphatases by zinc accounts for ERK1/2-dependent oxidative neuronal cell death. Molecular Pharmacology 74, 1141-1151. PMCID: PMC2575064
Signaling Pathways in Neurodevelopment: The life threatening, emotional and economic burdens of premature birth (~12% of pregnancies) have been greatly alleviated by antenatal treatment with synthetic glucocorticoids (sGCs). Antenatal sGCs accelerate tissue development reducing respiratory distress syndrome and intraventricular hemorrhage in premature infants, but they can affect developmental processes in the brain and trigger adverse behavioral and metabolic outcomes later in life. Most relevant to this proposal is our recent work published in a 2011 PNAS article (13) that identified a novel nongenomic signaling pathway mobilized by plasma membrane GRs that alters gap junction intercellular communication (GJIC), the synchrony of spontaneous calcium transients between coupled neural stem/progenitor cells (NSPC) and their proliferation. This led to examination of other pathways that modulate GJIC in NSPC (14). Additional mechanistic analysis of GR action in NSPCs identified a novel pathway of cross talk between nongenomic and genomic GR pathways that is brought about through differential site-specific phosphorylation of GR (15; article of special interest selected by journal editors). The presence of GR in NSPCs in the developing cerebral cortex provided the impetus for studies of differential sGC effects on the distinct stem and progenitor pools and behavioral effects in offspring exposed in utero to sGCs (16).
13. Samarasinghe RA, Di Maio R, Volonte D, Galbiati, F, Lewis M, Romero G, DeFranco DB (2011). Non-genomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation. Proc. Natl. Acad. Sci. USA 108, 16657-16662. PMCID: PMC3189065
14. Samarasinghe RA, Kanuparthi PS, Greenamyre JT, DeFranco DB, Di Maio R (2014). Transient muscarinic and glutamatergic stimulation of neural stem cells triggers acute and persistent changes in differentiation. Neurobiol. Dis. 70, 252-261. PMCID: PMC4152385
15. Peffer ME, Chandran UR, Luthra S, Volonte D, Galbiati F, Garabedian MJ, Monaghan-Nichols AP, DeFranco DB (2014). Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. Mol. Cell. Biol. 34, 2611-2623. PMCID: PMC4097667 (Article of Significant Interest Selected by Editors)
16. Tsiarli MA, Rudine A, Kendal N, Pratt MO, Krall R, Thiels E, DeFranco DB & Monaghan AP (2017). Antenatal dexamethasone exposure differentially affects distinct cortical neural progenitor cells and triggers long-term changes in cerebral architecture and behavior. Transl. Psychiatry 7, e1153. PMID: 28608856, PMCID: PMC5537650.