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SHP and Sin3A expression are essential for adamantyl-substituted retinoid-related molecule-mediated nuclear factor-kappaB activation, c-Fos/c-Jun expression, and cellular apoptosis.
Farhana L, Dawson MI, Dannenberg JH, Xu L, Fontana JA
Mol Cancer Ther. 2009 Jun;8(6):1625-35
Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
Dawson MI, Ye M, Cao X, Farhana L, Hu QY, Zhao Y, Xu LP, Kiselyuk A, Correa RG, Yang L, Hou T, Reed JC, Itkin-Ansari P, Levine F, Sanner MF, Fontana JA, Zhang XK
ChemMedChem. 2009 Jul;4(7):1106-19
Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity.
Dawson MI, Xia Z, Jiang T, Ye M, Fontana JA, Farhana L, Patel B, Xue LP, Bhuiyan M, Pellicciari R, Macchiarulo A, Nuti R, Zhang XK, Han YH, Tautz L, Hobbs PD, Jong L, Waleh N, Chao WR, Feng GS, Pang Y, Su Y
J Med Chem. 2008 Sep 25;51(18):5650-62
An adamantyl-substituted retinoid-derived molecule that inhibits cancer cell growth and angiogenesis by inducing apoptosis and binds to small heterodimer partner nuclear receptor: effects of modifying its carboxylate group on apoptosis, proliferation, and protein-tyrosine phosphatase activity.
Dawson MI, Xia Z, Liu G, Ye M, Fontana JA, Farhana L, Patel BB, Arumugarajah S, Bhuiyan M, Zhang XK, Han YH, Stallcup WB, Fukushi J, Mustelin T, Tautz L, Su Y, Harris DL, Waleh N, Hobbs PD, Jong L, Chao WR, Schiff LJ, Sani BP
J Med Chem. 2007 May 31;50(11):2622-39
Apoptosis induction by a novel retinoid-related molecule requires nuclear factor-kappaB activation.
Farhana L, Dawson MI, Fontana JA
Cancer Res. 2005 Jun 1;65(11):4909-17
Determinants of retinoid X receptor transcriptional antagonism.
Cavasotto CN, Liu G, James SY, Hobbs PD, Peterson VJ, Bhattacharya AA, Kolluri SK, Zhang XK, Leid M, Abagyan R, Liddington RC, Dawson MI
J Med Chem. 2004 Aug 26;47(18):4360-72
Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid.
Dawson MI, Zhang XK
Curr Med Chem. 2002 Mar;9(6):623-37
sp2-bridged diaryl retinoids: effects of bridge-region substitution on retinoid X receptor (RXR) selectivity.
Dawson MI, Hobbs PD, Jong L, Xiao D, Chao WR, Pan C, Zhang XK
Bioorg Med Chem Lett. 2000 Jun 19;10(12):1307-10
Marcia Dawson's Research Focus
Breast Cancer, Leukemia/Lymphoma, Type 2 Diabetes
The Dawson laboratory currently has two major research efforts. The first is optimizing the therapeutic index of a new group of compounds that induce cancer cell apoptosis (programmed cell death) and have therapeutic potential in the treatment of leukemia. A corollary goal is discerning how these compounds exert their apoptotic effects on cancer cells, in collaboration with Dr. Xiao-kun Zhang’s molecular biology group at Sanford-Burnham and Dr. Joseph A. Fontana’s cancer cell biology group at Wayne State University School of Medicine.
Marcia Dawson's Research Report
Optimizing Pro-apoptotic Compounds to Treat Cancer
We have found that on treatment with apoptosis-inducing compounds, cancer cells first experience increased levels of the cyclin kinase inhibitor p21WAF1/CIP1, followed by cell-cycle arrest. Cells then undergo the intrinsic form of apoptosis, which involves the release of cytochrome c and caspase activation.
Recently, the Zhang group found that expression of the transcription factor TR3 (nur77/NGFI-B) is induced ins some cancer cells. TR3 then exits the nucleus to interact with mitochondrial membrane-bound Bcl-2. The interaction between TR3 and Bcl-2 transforms the latter from a cytoprotective protein to one that fosters apoptosis. To facilitate these mechanistic studies, we designed and synthesized the tritiated analog of the parent compound, antagonists that prevent apoptosis, and other analogs that are only capable of inducing cell-cycle arrest. Recent research with the Fontana group led to identification of small heterodimer partner (SHP) as these compounds’ target. SHP is a unique orphan nuclear receptor that lacks a DNA-binding domain and modulates the activity of other transcription factors. These compounds are the first ligands identified for this receptor. Apoptosis induced by the interaction of these compounds with SHP requires the activation of the transcription factor NF-kB.
Retinoic Acid Analogs
Our second area of interest is the design and synthesis of synthetic analogs of retinoic acid that show selectivity for one of the retinoid receptor subtypes, of which there are six. Retinoic acid is the carboxylic acid analog of vitamin A and functions as a hormone by regulating such diverse processes as morphogenesis, cell differentiation, and cell proliferation. The retinoid receptors function as dimeric transcription factors that directly interact with responsive elements in gene promoters and in the presence of their retinoid ligands induce gene transcription. They also function indirectly by modulating the activity of other transcription factors. Because of the plethora of these effects, many signaling pathways are impacted. Thus, our objective is the identification of receptor dimer-selective retinoids that target specific signaling pathways. This research is also a collaborative effort with the Zhang group. Our group was the first to report retinoid X receptor-selective agonists. We have also identified several RXR antagonists and a new scaffold for RXR agonists.
About Marcia Dawson
Marcia I. Dawson earned her Ph.D. from Stanford University in 1968. She received postdoctoral training at California Institute of Technology, Harvard University, and Stanford Research Institute where she was appointed to staff and served in a progressive series of appointments culminating in Director of Drug Discovery, Bio-Organic Chemistry Lab, 1994–1999. She continued as Head of the Medicinal Medical Chemistry Department of the Molecular Medicine Research Institute, 1999–2000. Dr. Dawson was recruited to Sanford-Burnham Medical Research Institute in 2001.