Paul N. MacDonald, PhD

Associate Dean for Graduate Education
Department of Admissions and Programs
School of Medicine
Director, Post-baccalaureate Research Education Program
Professor
Department of Pharmacology
School of Medicine
Member
Molecular Oncology Program
Case Comprehensive Cancer Center

Paul MacDonald graduated from the Edinboro University of Pennsylvania with a BS in Chemistry in 1984. He then matriculated to Vanderbilt University School of Medicine as a Ph.D. student in the Department of Biochemistry where he studied the intestinal absorption of dietary vitamin A. While a PhD student, Dr. MacDonald discovered Lecithin-retinol Acyltranserase (LRAT), a key enzyme involved in vitamin A metabolism. Upon completion of his Ph.D. 1988, Dr. MacDonald moved to the University of Arizona for postdoctoral research training where he studied vitamin D, vitamin D receptor, and nuclear receptor-mediated transcription.  He continued his research in vitamin D as an NIH-funded, independent investigator; first, at Saint Louis University in the Department of Pharmacological and Physiological Sciences in 1993, and then at Case Western Reserve University in the Department of Pharmacology in 1999.

In 2013, Dr. MacDonald assumed a leadership role as the Associate Dean for Graduate Education in the School of Medicine at CWRU.  He has played integral teaching and administrative roles in both medical and graduate education for over 25 years.  He has trained seven Ph.D. students, two postdoctoral research associates, as well as numerous master's and undergraduate students throughout his research career. As Associate Dean, Dr. MacDonald recognizes the need and significance of providing optimal training experiences to our young researchers here at CWRU and across the nation.  Indeed, the primary goal of the Graduate Education Office at CWRU School of Medicine is to ensure that all graduate students, postdoctoral research associates, summer undergraduates, and other young scientists in our training environment are provided cutting-edge educational approaches, training experiences and individualized skill development in order to attain early success as leaders in academic, industrial, or other research-related professions.  He is also keenly interested and invested in diversity initiatives to improve minority representation in the biomedical workforce. 

Research Information

Research Interests

Vitamin D (Vit D) is required for normal calcium and phosphorus homeostasis and it is essential for the proper development and maintenance of bone. Vit D also exerts profound effects on cellular proliferation and differentiation, effectively inhibiting the proliferation of several breast and prostate tumor-derived, malignant cell lines. The biological effects of vit D are mediated through a nuclear protein termed the vitamin D receptor, or VDR. The VDR is a member of the superfamily of nuclear receptors that function as ligand-activated transcription factors. Thus, vit D and VDR together regulate the expression of specific genes or gene networks in mineral-regulating target organs such as the intestine, bone, kidney, and parathyroid glands. The global objective of my laboratory is to understand the molecular details and signaling mechanisms involved in VDR-mediated gene expression. 

The VDR alters gene expression by binding to specific DNA sequences in the promoter region of vitamin D responsive genes. VDR binds these specific DNA sequences as a heterodimer in association with another nuclear receptor termed retinoid X receptor (RXR). Thus, it is the VDR-RXR heterodimer bound to promoter DNA that ultimately controls the level of transcription of a particular vit D responsive gene. The signaling mechanisms that relay communications between the VDR-RXR heterodimer and the transcription complex are not well-understood. One current hypothesis states that additional proteins termed coactivators or corepressors are necessary for the transcriptional response. These coactivator proteins serve as macromolecular bridges between the VDR-RXR heterodimer and RNA polymerase II and a physical interaction of VDR with these transcriptional components is essential for vit D-mediated transcription to ensue. Current efforts in our laboratory are focused on identifying and characterizing the various contacts that occur between VDR and the transcription complex.

Research Projects

We have recently identified two key factors that may play an important role in this communication process. One contact is the interaction of VDR with transcription factor IIB (TFIIB), a component of the RNA polymerase II core transcription complex. This interaction represents a direct physical link between VDR and the polymerase and indeed, we have demonstrated that VDR interaction with TFIIB is an important step in the mechanism of vit D-mediated gene expression. Secondly, we recently cloned a cDNA encoding a novel nuclear protein that interacts with VDR and participates in vit D-mediated transcription. We have named this factor NCoA-62, for Nuclear receptor Coactivator with a molecular mass of 62,000 Da. Our most recent efforts are directed at understanding the molecular details through which VDR interaction with TFIIB and with NCoA-62 affect vit D-mediated transcription and the potential mechanistic interplay between these various transcription factors.

Publications

View Publications 

Ellison, T.E., Dowd, D.R., and MacDonald, P.N. Calmodulin-dependent kinase IV stimulates vitamin D receptor-mediated transcription (2005) Mol. Endocrinol. 19:2309-19.

Sutton, ALM, Zhang, X, Ellison, TI, and MacDonald, PN. The 1,25(OH)2D3-regulated transcription factor MN1 stimulates VDR-mediated-transcription and inhibits osteoblastic cell proliferation (2005) Mol. Endocrinol. 19:2234-44.

Milliken, EL, Zhang, X, Flask, C, Duerk, JL, MacDonald, PN, and Keri, RA. EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer (2005) Cancer Lett. 229:205-15.

Dhawan P, Peng X, Sutton AL, MacDonald PN , Croniger CM, Trautwein C, Centrella M, McCarthy TL, Christakos S. Functional cooperation between CCAAT/enhancer-binding proteins and the vitamin D receptor in regulation of 25-hydroxyvitamin D3 24-hydroxylase. Mol Cell Biol. 2005 25:472-87. 

Skorija K, Cox M, Sisk JM, Dowd DR, Macdonald PN , Thompson CC, Demay MB. Ligand-Independent Actions of the Vitamin D Receptor Maintain Hair Follicle HomeostasisMol Endocrinol. 2005 Apr;19(4):855-62. Epub 2004 Dec 9.

MacDonald PN , Dowd DR, Zhang C, Gu C. Emerging insights into the coactivator role of NCoA62/SKIP in Vitamin D-mediated transcriptionJ Steroid Biochem Mol Biol. 2004 89-90:179-86. Review. 

Zhang C, Dowd DR, Staal A, Gu C, Lian JB, van Wijnen AJ, Stein GS, MacDonald PN . Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicingJ Biol Chem. 2003 278:35325-36. 

Sutton, A.L.S. and MacDonald, P.N. Vitamin D: More Than a "Bone-a-Fide" Hormone (2003) Mol. Endocrinol. 17: 777-791. 

Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, MacDonald PN . Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcriptionJ Biol Chem. 2001 ;276:40614-20.

Kraichely DM, MacDonald, P.N. Confirming yeast two-hybrid protein interactions using in vitro glutathione-S-transferase pulldowns. In: Methods in Molecular Biology: Two-Hybrid Systems (MacDonald, P.N., ed.) 2001;177:135-150. 

MacDonald PN , Baudino TA, Tokumaru H, Dowd DR, Zhang C. Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcriptionSteroids . 2001 66:171-6. Review 

Kraichely, D.M., Collins, J., Delisle, R.K., and MacDonald, P.N. The autonomous transactivation domain in helix H3 of the vitamin D receptor is required for transactivation and coactivator interaction. J Biol Chem. 1999 May 14;274(20):14352-8.

Baudino, T.A., Kraichely, D.M., Jefcoat, S.C., Winchester, S.K., Partridge, N.C., and MacDonald, P.N. Isolation and characterization of a novel coactivator protein, NCoA-62, involved in vitamin D-mediated transcription. J. Biol. Chem. (1998) 273: 16434-16441.