Mark R. Haussler, PhD

Regents Professor, Basic Medical Sciences - The University of Arizona College of Medicine—Phoenix in partnership with Arizona State University

Professor, School of Life Sciences - Arizona State University

Professor, Departments of Physiology and Chemistry & Biochemistry - The University of Arizona

UA Office Phone: (602) 827-2100
Office: Building ABC1, Room 425
Email: haussler@u.arizona.edu

Education:

Post-Doc, Endocrine Signaling; University of Pennsylvania; 1968-1971

PhD; University of California at Riverside; 1968

Background:

After obtaining a B.S. in chemistry from UCLA and a Ph.D. in biochemistry at the University of California, Riverside, Dr. Haussler was introduced to molecular medicine during his postdoctoral tenure at the University of Pennsylvania, the oldest medical school in the USA. Applying basic science research to clinical problems has become a career and a passion for Dr. Haussler, coupled to his interest in the education of medical, graduate and undergraduate students. As a scholar-educator, he values the research-teaching interface, and believes that these two endeavors are mutually supportive in the improvement of human health. Impact in both arenas is achievable if one specializes, as he has in the molecular pathobiology of endocrine-related bone and mineral disorders, such as osteoporosis. Dr. Haussler's laboratory at The University of Arizona has been continuously funded by the NIH for over three decades, with a total of 61 equivalent years of R01 support from two grants, each of which achieved MERIT status. He has also taught first year medical students for a number of years, and was voted a Lifetime Educator of the Year by the students at The University of Arizona College of Medicine in 2003. In 2005, he became part of the exciting new task of partnering with ASU to launch a branch campus of The University of Arizona College of Medicine in the Phoenix downtown biomedical corridor. His laboratory moved from Tucson to the Arizona Biomedical Collaborative Building on the Phoenix campus in late Spring of 2007. In Phoenix, Dr. Haussler served (2005-2009) as the Founding Head of Basic Medical Sciences, an integrated department with faculty in all of the traditional (anatomy, biochemistry, cell biology, physiology, etc.) and new (biomedical informatics, human genetics, molecular biology, etc.) disciplines represented. The department's mission is to educate physicians for 21st Century Arizona, and to contribute to the biomedical research enterprise in Phoenix.

Research Interests:

The research in our laboratory is directed toward molecular understanding of the biological functions of the nuclear hormone receptor superfamily of ligand-regulated transcription factors, specifically the vitamin D receptor (VDR) and its heteropartner, the retinoid (vitamin A) X receptor (RXR). This binary receptor complex controls the expression of a number of genes, such as those for which the products mediate bone and mineral metabolism, epithelial cell differentiation and chemoprevention, xenobiotic detoxification, immunomodulation, endocrine gland function, and mammalian hair cycling within the context of normal skin development. Liganding of VDR with the renal hormone, 1,25-dihydroxyvitamin D, as well as low-affinity binders such as lithocholic acid, promotes association of VDR-RXR with vitamin D-responsive elements (VDREs) in targeted genes, followed by the attraction of transcriptional coactivators that modify chromatin as well as recruit RNA polymerase II. Recently, we have observed that 1,25-dihydroxyvitamin D-VDR-RXR induces: TRPV6, a channel that facilitates intestinal calcium absorption; LRP5, a Wnt ligand coreceptor that is anabolic to bone in its actions in osteoblasts; RANKL, an osteoclastogenic principle from osteoblasts that stimulates bone resorption; FGF-23, a novel hypophosphatemic hormone produced in osteoblasts that protects against ectopic calcification; and CYP3A4, a xenobiotic detoxifying enzyme. These findings provide new insight into the mechanisms whereby vitamin-D prevents osteoporosis, mediates normal bone remodeling, and prevents overmineralization as well as damage from certain lipid toxins. Mechanistically, the working hypothesis is that liganded VDR-RXR, docked on widely spaced VDREs in target genes, attracts comodulators into a localized "cloverleaf" complex with DNA looped out in chromatin, thus creating a nuclear machine for transcriptional control that is capable of simultaneously recruiting multiple cofactors to a polyprotein complex that initiates or represses gene transcription.

A second major area under investigation in our laboratory is deciphering the role of VDR in signaling the mammalian hair cycle, as well as in reducing the risk of cancers of the colon, prostate, breast, skin, plus other tissues possessing epithelial cells. With respect to the hair cycle, we have discovered that VDR-RXR cooperates with the nuclear corepressor, hairless (HR), and likely impacts Wnt signaling in keratinocytes. However, the HR-VDR-RXR gene targets in the hair follicle and skin are as yet unidentified, and the fact that, unlike VDR, RXR, and HR, vitamin D-derived ligands are not obligatory for normal hair growth remains to be explained. Nevertheless, the functions of VDR clearly have evolved in terrestial animals to include calcium acquisition which leads to a mineralized skeleton, thereby permitting locomotion in order to seek yet more calcium. In concert, protection against sun- and toxin-induced skin cancer via hair formation, plus direct effects of liganded VDR in skin cells that preclude carcinogenesis through enhanced detoxification, differentiation, DNA repair and/or apoptosis, renders VDR an important anticancer nuclear receptor.

PubMed Link:

Search PubMed for a complete listing of Dr. Haussler's publications

Selected Publications:

1. Haussler, M. R., Haussler, C. A., Bartik, L., Whitfield, G. K., Hsieh, J.-C., Slater, S., and Jurutka, P. W. Vitamin D receptor: Molecular signaling and actions of nutritional ligands in disease prevention. Nutr. Rev. 66, (Suppl. 2):S98-112 (2008).
2. Jurutka, P. W., Bartik, L., Whitfield, G. K., Mathern, D. R., Barthel, T. K., Gurevich, M., Hsieh, J.-C., Kaczmarska, M., Haussler, C. A., and Haussler, M. R. Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action and novel nutritional ligands. J. Bone Miner. Res. 22, Supplement 2, V2-V10 (2007).
3. Barthel, T. K., Mathern, D. R., Whitfield, G. K., Haussler, C. A., Hopper, H. A. IV, Hsieh, J.-C., Slater, Hsieh, G., Kaczmarska, M., Jurutka, P. W., Kolek, O.I., Ghishan, F. K., and Haussler, M. R. 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J. Steroid Biochem. Mol. Biol. 103, 381-388 (2007).
4. Jacobs, E. T., Haussler, M. R., and Martinez, M. E. Vitamin D activity and colorectal neoplasia: a pathway approach to epidemiological studies. Cancer Epidemiol. Biomarkers Prev. 14, 2061-2063 (2005).
5. Kolek, O. I., Hines, E. R., Jones, M. D., LeSuer, L. K., Lipko, M. A., Kiela, P. R., Collins, J. F., Haussler, M. R., and Ghishan, F. K. 1α,25-dihydroxyvitamin D3 up-regulates FGF23 gene expression in bone: the final link in a renal gastrointestinal-skeletal axis that controls phosphate transport. Am. J. Physiol., Gastrointest. Liver Physiol. 289, G1036-G1042 (2005).
6. Jurutka, P. W., Thompson, P. D., Whitfield, G. K., Eichhorst, K. R., Hall, N., Encinas Dominguez, C., Hsieh, J.-C., Haussler, C. A., and Haussler, M. R. Molecular and functional comparison of 1,25-dihydroxyvitamin D3 and the novel vitamin D receptor ligand, lithocholic acid, in activating transcription of cytochrome P450 3A4. J. Cell. Biochem. 94, 917-943 (2005).
7. Whitfield, G. K., Jurutka, P. W., Haussler, C. A., Hsieh, J.-C., Barthel, T. K., Jacobs, E. T., Encinas Dominguez, C., Thatcher, M. L., and Haussler, M. R. Nuclear vitamin D receptor: Structure-function, molecular control of gene transcription and novel bioactions. In Vitamin D, Second Edition D. Feldman, J. W. Pike and F. Glorieux, eds., Elsevier Academic Press, San Diego, pp. 219-261 (2005).
8. Hines, E. R., Kolek, O. I., Jones, M. D., Serey, S. H., Sirjani, N. B., Kiela, P. R., Jurutka, P. W., Haussler, M. R., Collins, J. F., and Ghishan, F. K. 1,25-dihydroxyvitamin D3 downregulation of PHEX gene expression is mediated by apparent repression of a 110 kDa transfactor that binds to a polyadenine element in the promoter. J. Biol. Chem. 279, 46406-46414 (2004).
9. Hsieh, J. C., Sisk, J. M., Jurutka, P. W., Haussler, C. A., Slater, S. A., Haussler, M. R., and Thompson, C. C. Physical and functional interaction between the vitamin D receptor and hairless corepressor, two proteins required for hair cycling. J. Biol. Chem. 278, 38665-38674 (2003).
10. Whitfield, G. K., Dang, H. T. L., Schluter, S. F., Bernstein, R. M., Bunag, T., Manzon, L. A., Hsieh, G., Encinas-Dominguez, C., Youson, J. H., Haussler, M. R., and Marchalonis, J. J. Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth. Endocrinology 144, 2704-2716 (2003).