Broadly, I am interested in the cell biology of a superfamily of ligand-induced
transcription factors that regulate expression of specific genes. Members of
this superfamily bind to promoter regions of specific genes and either activate
(after binding to their ligands and to co-activator) or repress (with co-repressor
bound) the expression of target genes. Specifically, I am studying two closely
related transcription factors, liver X receptors (LXR) α and β. LXR α
and LXR β regulate transcription of genes that are important for cholesterol
metabolism, lipogenesis, and other metabolic pathways. Despite their high similarity
LXR α and LXR β regulate transcription in part selectively. This selectivity
can potentially be utilized to develop selective drugs for treatment of cholesterol-related
diseases. However, the molecular mechanisms of this selectivity are obscure.
The nucleus is a discrete compartment for transcription of the eukaryotic genome. This allows gene expression to be regulated in response to external stimuli by altering the nucleocytoplasmic and the intranuclear distribution of transcription factors including LXR α and LXR β. Our hypothesis is that selective regulation of nuclear localization of LXR α and LXR β contributes to their selective functions. This hypothesis is supported by our recent data. Nuclear localization of proteins is regulated by nuclear retention, nuclear export, and nuclear import. We recently showed that nuclear localization of LXR α and β is differentially regulated. Both rate of nuclear retention and nuclear export is different for LXR α and LXR β. We identified nuclear localization sequences (NLS) in LXR α and LXR β and found that nuclear import is differentially regulated in both receptors.
Currently, we are pursuing the molecular mechanisms of differences in regulation of nuclear localization and function of LXR α and LXR β. Nucleo-cytoplasmic trafficking allows dynamic interactions of LXR α and LXR β with ligands, promoter regions of specific genes, and proteins. Our research goals include identifying such interactions. Putative interacting proteins comprise nuclear import receptors binding to the identified NLS and nuclear export receptors binding to nuclear export sequences (NES). We will identify NES in LXR a and LXR ß. We are currently identifying import and export receptors mediating nuclear import and nuclear export of LXR α and LXR β. Other putative interacting proteins are co-repressors and co-activators. We will study the importance of such interactions for differences in nuclear retention of LXR α and LXR β. Other projects aim at identifying as yet unknown interacting proteins, studying the role of LXR phosphorylation, and analysing promoter regions of LXR regulated genes. Results of these projects will contribute to a dynamic model of various interactions that regulate nuclear localization as well as function of LXR α and LXR β. Such a model will contribute to our understanding of the molecular mechanisms underlying selective activation of transcription by LXR α and LXR β.
Selected Publications
K. Prüfer, Jeanne Boudreaux: Nuclear Localization of Liver X Receptor a and ß is Differentially Regulated, J. Cell Biochemistry (2006), in press
Kirsten Prüfer, Julia Barsony: Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor. Molecular Endocrinology 16 (2002) 1738-1751
Julia Barsony, Kirsten Prüfer: Vitamin D Receptor and Retinoid X Receptor Interactions in Motion. Vitamins and Hormones 65 (2002) 345-376
Kirsten Prüfer, Claudia Schröder, Krisztina Hegyi, Julia Barsony: Enhanced Degradation of Retinoid X Receptors in Osteosarcoma Cells Prevents the Antiproliferative Effects of Calcitriol and Retinoic Acid. Molecular Endocrinology 16 (2002) 961-976
Kirsten Prüfer, Attila Racz, Grace C. Lin and Julia Barsony: Dimerization with Retinoid X Receptors Promotes Nuclear Localization and Subnuclear Targeting of Vitamin D Receptors. Journal of Biological Chemistry 275 (2000) 41114-41123