Paul N. MacDonald, PhD
Associate Professor, Pharmacologypnm2@case.edu 216.368.2466 (o) 216.368.3395 (f)
Member, Molecular Oncology Program
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.
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 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.