Research Interests:
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 [1–3]. A corollary goal is discerning how these compounds exert their apoptotic effects on cancer cells in collaboration with the molecular biology group of Professor Xiao-kun Zhang at the Institute and the cancer cell biology group of Dr. Joseph A. Fontana at the Wayne State University School of Medicine [4–9]. Thus far, we know that on treatment with these compounds the cancer cells first undergo cell-cycle arrest [10], which is preceded by an increase in the levels of the cyclin kinase inhibitor p21WAF1/CIP1 [11]. Cells then undergo the intrinsic form of apoptosis, which involves the release of cytochrome c and caspase activation. Recently, the Zhang group found that in some cancer cells the expression of the transcription factor TR3 (nur77/NGFI-B) is induced. TR3 then exits the nucleus to interact with mitochondrial membrane-bound Bcl-2 [12]. 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 have designed and synthesized the tritiated analog of the parent compound [7], antagonists that prevent apoptosis [13,14], and other analogs that are only capable of inducing cell-cycle arrest. Recent research with the Fontana group led to identifying the target for these compounds as small heterodimer partner (SHP) [14], 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 [15]. Apoptosis induced by the interaction of these compounds with SHP requires the activation of the transcription factor NF-kB [16].
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 [17], 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. The Dawson group was the first to report retinoid X receptor-selective agonists [17–20]. We have also identified several RXR antagonists [21].
Track(s):
Molecular Pathology
BMS Focus Areas:
Cancer Biology
Structural Chemical Biology
Stem Cells
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