Biochemistry

Dennis B. Lubahn

Professor of Biochemistry
Principal Investigator and Director of the MU Center for Phytonutrient and Phytochemical Studies

E-mail:lubahnd@missouri.edu

Office: 110A Animal Science Center

Mail: Biochemistry
110A Animal Science Center
University of Missouri
Columbia, MO 65211

Phone: 573-884-6781

Fax: 573-882-6827

Lab: 573-882-7748

Lab site: http://www.phyto-research.org/

Educational background

Notable honors and service

• Director, Botanical Center
• Pew Scholar in Biomedical Sciences, 1989-92

Research description

I am the principal investigator and director of the MU Center for Phytonutrient and Phytochemical Studies. The MU Center for Phytonutrient and Phytochemical Studies is a comprehensive research program that investigates the molecular mechanisms of phytochemicals and phytonutrients in human disease. The Center fosters research to determine the safety and efficacy of botanicals or plants in the treatment of human disease. The Center's current research investigates molecular mechanisms of the phytoestrogen, antioxidant, and polyphenol actions in three human diseases: Cancer, Neurodegenerative disease and Immune-mediated abnormalities. (Please refer to the Botanical Center web site at www.phyto-research.org for more detailed information.)

My long-term research interests involve the understanding of the mechanism of action of the sex steroids and their receptors, in particular the estrogen receptors. My lab's research goals use the estrogen receptor-alpha (ERα) and estrogen receptor-beta (ERβ)-minus mice to look for new estrogen response pathways (i.e. novel estrogen receptors) and to find novel functional roles for the classic estrogen receptor. This is a hot research area for me because of the increased interest in environmental estrogens and our observations that some of these environmental estrogens are inducing responses in the ERα -minus mice. These estrogen-induced responses in an ERα-minus mouse are indicative of the existence of a potential new estrogen receptor, "ER-gamma". Other major interests in my laboratory are: 1) The trinucleotide repeat genetic diseases, primarily because many trinucleotide repeats with unknown function are found in several of the steroid receptor genes; and, 2) The imprinting signals of endocrine disrupters, such as the environmental estrogens, especially those potentially acting via DNA-methylation signaling pathways.

The main long-term goals of my research program are to find novel functions for estrogens and the receptors, and then to identify the molecular mechanisms mediating these functions. To pursue these goals, we "knocked out" the estrogen receptor-alpha (ERα) gene in mice via homologous recombination and asked the following question: Would an ERα-minus mouse respond to any known estrogen, estrogen metabolite or exogenous (natural or synthetic) estrogen analog, if it lacked the classic full length ERα protein? If ERα -minus mice did respond, then we would know that at least one estrogen response protein other than ER exists. The working hypothesis was that several non-ERα /non-ERβ response proteins exist and that in transgenic ERα-minus mice we would see a response to estrogens, such as the catechol estrogens.

We have found in ERα-minus mice a uterine lactoferrin mRNA response to 4-hydroxyestradiol, methoxychlor and kepone, but not to estradiol. We now hypothesize that: A) 4-hydroxyestradiol and these other biologically important estrogens work through their own unique non-classical, non-ERα/non-ERβ estrogen response proteins or receptors; and B) NCER "receptors" can be readily characterized in the ER-minus mouse backgrounds. Using these mouse model system we are characterizing the 4-hydroxyestradiol and methoxychlor responses and the putative 4-hydroxyestradiol and methoxychlor receptors. Specifically: Aim #1, Characterize lactoferrin mRNA response to 4-hydroxyestradiol and methoxychlor in ER-minus mice; Aim #2, Characterize the putative 4-hydroxyestradiol and methoxychlor receptors in ER-minus cell cultures; Aim #3, Characterize potential responses to estradiol in ER-minus mice; Aim #4, Characterize estrogen responses unique to 4-hydroxyestradiol and methoxychlor; and Aim #5, Clone the putative 4-hydroxyestradiol and methoxychlor receptors.

Our working hypothesis is that estrogen responses in behavior, in bone, in glucose homeostasis, and in the reproductive, immune, and cardiovascular systems may not be mediated exclusively by the classical ERα or the ERβ proteins, but by additional non-classical estrogen response (NCER) proteins. Studying specific mouse NCER proteins will lead to a better understanding of estrogen's developmental, physiological, behavioral, and biochemical roles in humans.

Selected publications

Brown M., Ning J., Ferreira J.A., Bogener J.L., Lubahn D.B. (2009) Estrogen receptor-alpha and -beta and aromatase knockout effects on lower limb muscle mass and contractile function in female mice. Am. J. Physiol. Endocrinol. Metab. 296(4): E854-61

Shenouda N.S., Sakla M.S., Newton L.G., Besch-Williford C., Greenberg N.M., MacDonald R.S., Lubahn D.B. (2007) Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo. Endocrine 31(1): 72-81

Zhou W., Liu Z., Wu J., Liu J.H., Hyder S.M., Antoniou E., Lubahn D.B. (2006) Identification and characterization of two novel splicing isoforms of human estrogen-related receptor beta. J. Clin. Endocrinol. Metab. 91(2): 569-79

Lambert K.C., Curran E.M., Judy B.M., Milligan G.N., Lubahn D.B., Estes D.M. (2005) Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J. Immunol. 175(9): 5716-23

Pamidimukkala J., Xue B., Newton L.G., Lubahn D.B., Hay M. (2005) Estrogen receptor-alpha mediates estrogen facilitation of baroreflex heart rate responses in conscious mice. Am. J. Physiol. Heart Circ. Physiol. 288(3): H1063-70

Philips BJ, Ansell PJ, Newton LG, Harada N, Honda S, Ganjam VK, Rottinghaus GE, Welshons WV, Lubahn DB. (2004) Estrogen receptor-independent catechol estrogen binding activity: protein binding studies in wild-type, Estrogen receptor-alpha KO, and aromatase KO mice tissues. Biochemistry. 43: 6698-6708.

Employment opportunities

Postdoctoral opportunities

Research areas: Biochemical genetics and epigenetics of estrogens and related receptors.

How to apply:

Electronic submission is encouraged, e-mail to lubahnd@missouri.edu

Applicants should send CV and names of two references to:
Dr. Dennis B. Lubahn
Biochemistry
110A Animal Science Center
University of Missouri
Columbia, MO 65211