References:
- Liu YY, Collins ED, Norman AW, Peleg S (1997) Differential interaction of 1alpha,25-dihydroxyvitamin D3 analogues and their 20-epi homologues with the vitamin D receptor. J Biol Chem 272:3336-45.
- Liu Y-Y, Nguyen C, Peleg S (2000) Regulation of ligand-induced heterodimerization and coactivator interaction by the activation function-2 domain of the vitamin D receptor. Mol Endocrinol 14:1776-87.
- Gardezi SA, Nguyen C, Malloy PJ, Posner GH, Feldman D, Peleg S (2001) A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D(3). J Biol Chem 276:29148-56.
- Yang J, Fizazi K, Peleg S, Sikes CR, Raymond AK, Jamal N, Hu M, Olive M, Martinez LA, Wood CG, Logothetis CJ, Karsenty G, Navone NM. (2001) Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Res 61:5652-9.
- Peleg S, Uskokovic M., Ahene A, Vickery B, Avnur Z. (2002) Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats. Endocrinology
143:1625-36 - Ismail A, Nguyen CV, Ahene A, Fleet JC, Uskokovic MR, Peleg S (2004) Effect of cellular environment on the selective activation of the vitamin D receptor by 1alpha,25-dihydroxyvitamin D3 and its analog 1alpha -fluoro-16-ene-20-epi-23-ene-26,27-bishomo-25-hydroxyvitamin D3 (Ro-26-9228). Mol Endocrinol (4):874-87.
- Peleg S, Khan F, Navone NM, Cody DD, Johnson EM, Pelt CS, Posner GH (2005) Inhibition of prostate cancer-meditated osteoblastic bone lesions by the low-calcemic analog 1alpha -hydroxymethyl-16-ene-26,27-bishomo-25-hydroxy
vitamin D3. J Steroid Biochem Mol Biol 97:203-211. - Peleg S, Petersen KS, Suh BC, Dolan P, Agoston ES, Kensler TW, Posner GH
(2006) Low-calcemic, highly antiproliferative, 1-difluoromethyl hybrid analogs of the natural hormone 1alpha,25-dihydroxyvitamin D3: design, synthesis, and preliminary biological evaluation. J Med Chem. 49(25):7513-7
Sara Peleg, Ph.D.
Associate Professor
MD Anderson, (713) 500 - 7485
speleg@mdanderson.org
Mechanisms for cell- and gene-specific activation of nuclear receptors
Nuclear receptors are transcription factors that function as transmitters of signals delivered by small lipophilic molecules such as steroid hormones and retinoids. These signals regulate embryonic development, cellular differentiation and organ physiology. Our research interests focus on the nuclear receptor for vitamin D. The physiological role of this vitamin/hormone is to regulate calcium homeostasis, but in pharmacological amounts it can inhibit cell growth and induce differentiation and thereby be used to treat leukemia, breast and prostate cancer. Our laboratory is interested in segregating the calcium regulating activities and growth inhibitory actions of vitamin D, because large amounts of vitamin D induce toxic hypercalcemia. We approach this challenge by manipulating and fine-tuning vitamin D receptor action with synthetic analogs of vitamin D. We explore how the natural hormone and its synthetic analogs fit into the ligand-binding pocket of the receptor. We also investigate the effect of analogs binding on the shape of the outer surface of the receptor. Changes in the surface of the vitamin D receptor have a direct impact on its interaction with cellular proteins that modulate the level and spectrum of its transcriptional activities. We translate our in vitro findings into preclinical studies in animal models of osteoporosis, metastatic bone disease and hereditary bone disease that is caused by defects in the vitamin D receptor. These directions of our research provide a foundation for the design of vitamin D analogs that have sufficient target cell and target gene specificity to be both potent and safe drugs for treatment of human disease.
A tutorial in my laboratory will provide experience in: recombinant DNA techniques including cloning, gene transfer and gene expression, protein-DNA and protein-protein interaction assays and structure/function analysis of transcription factors.
