Margaret Clagett-Dame, Ph.D.Margaret Clagett-Dame, Ph.D.

Biochemistry Addition Rm 241
433 Babcock Drive
Madison, WI 53706
608-262-3450
dame@biochem.wisc.edu

Emphasis Group:
Biochemical & Molecular Nutrition

Principal Research Interest:
Molecular mechanism of action of vitamin A in embryonic development, vitamin A and neuronal survival and differentiation, retinoids in chemoprevention and chemotherapy

Research Summary:
Research in this laboratory is focused on the molecular mechanism of action of vitamin A and its metabolites. Much of the laboratory is devoted to understanding how vitamin A functions during embryogenesis, with particular emphasis on neural development. A second focal area is the use of retinoids (natural or synthetic compounds related to A) in chemoprevention and chemotherapy.

Embryonic development is disrupted both in vitamin A deficiency and in excess. Using the rat embryo as a model, we find that vitamin A deficiency during early embryogenesis leads to defects in the patterning of the hindbrain, heart and skeleton; whereas a deficiency imposed at later times leads to a host of anomalies in the eye, kidney, diaphragm, heart, lung and urogenital system. Many of these same developing systems are subject to malformation in retinoid excess. Because retinoids are used therapeutically, embryotoxicity is a real concern when using these compounds at pharmacological concentrations. Before the therapeutic potential of retinoids can be fully realized, it will be necessary to understand how vitamin A and its metabolites function normally at the cellular and molecular level, and how normal function is disrupted in toxicity.

Retinoids act, in part, by binding to two families of nuclear retinoid receptors (retinoic acid receptors, RARs; and retinoid-X receptors, RXRs). These receptors function as ligand-activated transcription factors that modulate gene transcription. The highest affinity ligand for the RAR is all-trans retinoic acid (atRA). A major focus of the lab has been to delineate the atRA-responsive genes whose expression is altered in retinoid deficiency and/or excess and to establish how these changes lead to an abnormal phenotype. Very recently, we have identified several at RA-responsive genes by screening subtractive libraries from retinoid treated and untreated cultures of human neuroblastoma cells and primary cultures of embryonic sympathetic neurons. We are currently studying the function of these genes in neuronal survival, cellular differentiation and embryonic development.

We are also devoting considerable effort to the development and study of retinoids that may be useful in medical applications. Recent studies suggest that a stable carbon linked analog of 4-hydroxyphenylretinamide as well as several glucuronide retinoid conjugates are useful in chemoprevention and chemotherapy, and have reduced toxicity relative to the parent compounds. We are currently studying the mechanism of action of these novel retinoids in cancer cell lines as well as in rats with DMBA induced mammary tumors

Representative Publications

Anding AL, Chapman JS, Barnett DW, Curley RW Jr, Clagett-Dame M. The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-
binding component 3 (PUMA) and apoptosis that is caspase-dependent and independent of the retinoic acid receptor. Cancer Res. 2007 Jul 1;67(13):6270-7.

Slatopolsky E, Finch JL, Brown AJ, Ritter CS, Mizobuchi M, Plum LA, Clagett-Dame M, Sicinski RR, DeLuca HF. Effect of 2-methylene-19-nor-(20S)-1 alpha-hydroxy-bishomopregnacalciferol (2MbisP), an analog of vitamin D, on secondary hyperparathyroidism. J Bone Miner Res. 2007 May;22(5):686-94.

Thomson B, Ahrens JM, Ntambi JM, DeLuca HF, Clagett-Dame M. 2-Methylene-19-nor-1alpha-hydroxyvitamin D3 analogs inhibit adipocyte differentiation and PPARgamma2 gene transcription. Arch Biochem Biophys. 2007 Apr 15;460(2):192-201.

DeLuca HF, Plum LA, Clagett-Dame M. Selective analogs of 1alpha,25-dihydroxyvitamin D3 for the study of specific functions of Vitamin D. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):263-8.