Transcriptional Regulation and Epigenetics

Dr Paul Thompson

Lecturer in Molecular Biology

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Dr Paul Thompson

Academic and Professional Qualifications:

Career Summary:

Research interests

The primary emphasis of my research is focused on elucidating the gene regulatory pathways and molecular mechanisms that mediate the plethora of physiological responses to the lipophilic nutrient vitamin D.

The activities of the active metabolite of vitamin D, that is 1,25(OH)2D3 (1,25D), are mediated through its specific vitamin D receptor (VDR), a member of the same superfamily of ligand-inducible transcription factors that include the steroid and retinoid/thyroid hormone receptors. Although the classical actions of 1,25D-VDR are associated with the maintenance of calcium/phosphate ion homeostasis, within the past few years experimental evidence has suggested that liganded VDR may serve as a modulator of exogenous and endogenous toxins.

The current research within our group falls into two broad themes with respect to nuclear receptor-mediated gene activation;

- We are currently studying the mechanisms by which VDR can function as a chemoprotective agent in tissues such as prostate and colon, through the induction of genes related to the metabolism and transport of harmful xenobiotic compounds and bile acids. Through revealing the network of chemoprotective genes that are regulated through VDR we can gain important mechanistic insights into how vitamin D can protect against the development of prostate and colon cancers.
- In collaboration with Dr Karsten Melcher, are investigating a number of novel accessory protein factors as potential modulators of nuclear receptor signalling that we have identified through an extensive yeast two hybrid screening procedure using liganded VDR as bait. Through elucidating the role of these interacting proteins, we can gain important insights as to how VDR and other nuclear receptors can initiate and regulate the expression of specific hormone-responsive target genes and contribute towards the development of gene-selective agonists/antagonists of nuclear receptor function.

Selected publications:

Jurutka, P.W.* and Thompson, P.D.*, Whitfield, G.K., Eichhorst, K.R., Hall, N., Dominguez, C.E., Hsieh, J.C., Haussler, C.A. and Haussler M.R. (2005) “Molecular and functional comparison of 1,25-dihydroxyvitamin D(3) and the novel vitamin D receptor ligand, lithocholic acid, in activating transcription of cytochrome P450 3A4†. J Cell Biochem, 94, 917-43. IF: 2.946

Otte, K., Kranz, H., Kober, I., Thompson, P., Hoefer, M., Haubold, B., Remmel,B., Voss, H., Kaiser, C., Albers, M., Cheruvallath, Z., Jackson, D., Casari, G., Koegl, M., Pääbo, S., Mous, J., Kremoser, C. and Deuschle U. (2003) “Identification of FXRb as a novel mammalian nuclear receptor sensing lanosterol†, Mol Cell Biol. 23, 864-72. IF: 7.822

Hsieh, J.C., Whitfield, G.K., Jurutka, P.W., Haussler, C.A., Thatcher, M.L., Thompson, P.D., Dang, H.T., Galligan, M.A., Oza, A.K., Haussler, M.R. (2003) “Two basic amino acids C-terminal of the proximal box specify functional binding of the vitamin D receptor to its rat osteocalcin deoxyribonucleic acid-responsive element†, Endocrinology, 144,5065-80. IF: 5.151

Thompson, P.D.*, Jurutka, P.W.*, Kerr Whitfield, G., Myskowski, S.M., Eichhorst, K.R., Encinas Dominguez, C., Haussler, C.A, Haussler, M.R. (2002) “Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements†, Biochem Biophys Res Commun. 299,730-8. IF: 2.904

Jurutka, PW, MacDonald, PN, Nakajima, S, Hsieh, JC, Thompson, PD, Whitfield, GK, Galligan, MA, Haussler, CA, Haussler M.R. (2002) Isolation of baculovirus-expressed human vitamin D receptor: DNA responsive element interactions and phosphorylation of the purified receptor. J Cell Biochem. 85,435-57. IF: 2.946

Thompson, PD, Remus, LS, Hsieh, J-C, Jurutka, PW, Whitfield, GK, Galligan, MA, Encinas- Dominguez, C, Haussle,r CA, and Haussler, M.R. (2001) “Distinct Activation Function-2 (AF-2) Residues in RXR Determine Transactivation in the Context of VDR-RXR Heterodimers versus RXR-RXR Homodimers†. J Mol Endocrinol. 27, 211-227 IF: 3.855