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Mark R. Haussler, PhD

Regents Professor, Basic Medical Sciences
Valley of the Sun Endowed Professor
Professor, Departments of Physiology and Chemistry & Biochemistry - The University of Arizona
Member, Sarver Heart Center
Phone: 
(602) 827-2100
UA Office Building and Room : 
Building ABC1, Room 425
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 allopathic 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. In 2010, Dr. Haussler was appointed SRP Valley of the Sun Endowed Professor, the first named Chair at the College of Medicine-Phoenix. 

 

Research

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.

Mark R. Haussler, PhD
Mark R. Haussler, PhD
Mark R. Haussler, PhD
Mark R. Haussler, PhD
Mark R. Haussler, PhD
Selected Publications

PubMed Link:

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

  1. Hsieh, J.-C., Estess, R. C., Kaneko, I., Whitfield, G. K., Jurutka, P. W., and Haussler, M. R.  Vitamin D receptor-mediated control of Soggy, Wise, and Hairless gene expression in keratinocytes. J. Endocrinol. 220(2): 165-178 (2014). First published online, November 4, 2013. DOI 10.1530/JOE-13-0212.
  2. Hoss, E., Austin, H. R., Battie, S. F., Jurutka, P. W., Haussler, M. R., and Whitfield, G. K.  Control of late cornified envelope genes relevant to psoriasis risk: upregulation by 1,25-dihydroxyvitamin D3 and plant-derived delphinidin. Arch. Dermatol. Res. 305(10): 867-868 (2013). First published online, July 10, 2013. DOI 10.1007/s00403-013-1390-1.
  3. Jacobs, E. T., Van Pelt, C., Forster, R. E., Zaidi, W., Hibler, E. A., Galligan, M. A., Haussler, M. R., and Jurutka, P. W.  CYP24A1 and CYP27B1 polymorphisms modulate vitamin D metabolism in colon cancer cells.  Cancer Res. 73(8): 2563-2573 (2013).
  4. Saini, R. K., Kaneko, I., Jurutka, P. W., Forster, R., Hsieh, A., Hsieh, J.-C., Haussler, M. R., and Whitfield, G. K.  1,25-Dihydroxyvitamin D3 regulation of fibroblast growth factor-23 expression in bone cells: Evidence for primary and secondary mechanisms modulated by leptin and IL-6. Calcif. Tissue Int. 92(4): 339-353 (2013). First published online, December 22, 2012.  DOI 10.1007/s00223-012-9683-5.
  5. Jurutka, P. W., Whitfield, G. K., Forster, R., Batie, S., Lee, J., and Haussler, M.R.  Vitamin D: A fountain of youth in gene regulation.  In Vitamin D: Oxidative Stress, Immunity, and Aging. A. F. Gombart, ed., CRC Press, New York, pp. 3-35 (2013).
  6. Haussler, M. R., Whitfield, G. K., Kaneko, I., Haussler, C. A., Hsieh, D., Hsieh, J.-C., and Jurutka, P. W.  Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92(2): 77-98 (2013). First published online, July 11, 2012.  DOI 10.1007/s00223-012-9619-0.
  7. Haussler M. R., Whitfield G. K. , Kaneko I., Forster R., Saini R., Hsieh J.-C., Haussler C. A., and Jurutka P. W.  The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev. Endocr. Metab. Disord. 13(1): 57-69 (2012).
  8. Forster R. E., Jurutka P. W., Hsieh J.-C., Haussler C. A., Lowmiller C. L., Kaneko I., Haussler M. R., and Whitfield G. K.  Vitamin D receptor controls expression of the anti-aging klotho gene in mouse and human renal cells. Biochem. Biophys. Res. Commun. 414(3): 557-562 (2011).
  9. Haussler M. R., Jurutka P. W., Mizwicki M., and Norman A. W. Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2vitamin D3: genomic and non-genomic mechanisms. Best Pract. Res. Clin. Endocrinol. Metab. 25(4): 543-559 (2011). PMID: 21872797.
  10. Haussler, M. R., Whitfield, G. K., Haussler, C. A., Hsieh, J.-C., Jurutka, P. W.  Nuclear vitamin D receptor: Natural ligands, molecular structure-function, and transcriptional control of vital genes.  In Vitamin D, Third Edition D. Feldman, J. W. Pike and J. Adams, eds., Elsevier Academic Press, San Diego, pp. 137-170 (2011).
  11. Hsieh, J.-C., Slater S. A., Whitfield G. K., Dawson J. L., Hsieh G., Sheedy C., Haussler C.A., and Haussler M. R.  Analysis of hairless corepressor mutants to characterize molecular cooperation with the vitamin D receptor in promoting the mammalian hair cycle. J. Cellular Biochem. 110(3), 671-686 (2010). PMID: 20512927.
  12. Haussler, M. R.,Haussler, C.A., Whitfield, G. K., Hsieh, J.-C., Thompson, P.D., Barthel, T. K., Bartik, L., Egan, J. B., Wu, Y., Kubicek, J. L., Lowmiller, C. L., Moffet, E. W., Forster, R. E., and Jurutka, P. W.  The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging.  J. Steroid Biochem. Mol. Biol.  121, 88-97 (2010) PMID: 20227497.
  13. Bartik, L., Whitfield, G. K., Kaczmarska, M., Lowmiller, C. L., Moffet, E. W., Furmick, J. K., Hernandez, Z., Haussler, C. A., Haussler, M. R., and Jurutka, P. W.  Curcumin: A novel nutritionally-derived ligand of the vitamin D receptor with implications for colon cancer chemoprevention.  J. Nutr. Biochem. 21(12), 1153-1161(2010).
  14. Egan, J. B., Thompson, P. A., Vitanov, M. V., Bartik, L., Jacobs, E. T., Haussler, M. R., Gerner, E. W., and Jurutka, P. W.  Vitamin D receptor ligands, APC, and the VDR Fok1 polymorphism collectively modulate beta-catenin activity in colon cancer cells.  Mol. Carcinog. 49, 337-352 (2010) PMID: 20043299.
  15. 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).