My research interests focus on developing and utilizing novel gene silencing and activating technology to study nuclear receptor signaling pathways. We have discovered that genes can be selectively silenced or activated by directly targeting chromosomal DNA with duplex RNA. We are using this technology to study the biological consequences of silencing or activating nuclear receptors in cancer cells. Nuclear receptors are ligand-activated transcription factors that are involved in a myriad of cell signaling pathways and represent a class of therapeutic targets in the treatment of disease. The approach is a powerful way to identify and dissect crosstalk between these signaling pathways.
One goal is to better understand the role of progesterone receptors in cancer. Normal expression of PR mediates the function of the hormone progesterone and is important for reproduction and other crucial physiologic function. Altered expression of PR has been associated with increased cancer risk and poor prognosis, although the role of PR in tumorigenesis has not been elucidated. Using multiple gene silencing strategies, we have uncovered an underlying feedback mechanism for maintaining progesterone receptor balance and normal progesterone signaling. We have also observed that silencing of the PR gene disrupts normal inflammatory responsiveness and contributes to the invasiveness of cancer cells and subsequent tumorigenesis by altering the expression of cytoskeletal proteins that control cell morphology.
We are also applying the technology to probe the structure and functional elements within TATA-less promoters to better understand the intricate ways in which nuclear receptors are regulated at the level of transcription in the context of intact chromosomes.
RESEARCH INTERESTS
Developing novel technology to selectively activate or silence genes within chromosomal DNA
Recognition of chromosomal DNA by synthetic molecules
Mechanisms controlling recognition of DNA and gene transcription
Using new technology to study nuclear hormone receptors
RECENT PUBLICATIONS
Janowski, B. A., Kaihatsu, K., Huffman, K. E., Schwartz, J., Ram, R., Hardy, D., Mendelson, C.R., and Corey, D. R., "Inhibiting transcription of chromosomal DNA with antigene peptide nucleic acids." Nature Chemical Biology, 1:210-215, September 2005
Janowski, B. A., Huffman, K. E., Schwartz, J., Ram, R., Hardy, D., Shames, D. S., Minna, J. D., and Corey, D. R., "Inhibiting gene expression at transcription start sites in chromosomal DNA with antigene RNAs." Nature Chemical Biology, 1:216-222, September 2005
Janowski, B.A., Huffman, K.E., Schwartz, J.C., Ram, R., Shames, D.S., Minna, J.D., Corey, D.R., "Involvement of AGO1 and AGO2 in mammalian transcriptional gene silencing" Nature Structural and Molecular Biology, 13:787, September 2006
Janowski, B.A., Younger, S.T., Hardy, D.B., Ram, R., Huffman, K.E., Corey, D.R., "Activating gene expression in mammalian cells with promoter-targeted duplex RNAs" Nature Chemical Biology, 3:166, March 2007
SIGNIFICANT PUBLICATIONS
Janowski, B. A., "The hypocholesterolemic agent LY295427 upregulates INSIG-1, identifying the INSIG-1 protein as a novel mediator of cholesterol homeostasis through SREBP." Proceedings of the National Academy of Sciences, 99:12675-80, October 2002
Janowski, B.A., Grogan, M.J., Jones, S., Wisely, G.B., Kliewer, S.A., Corey, E.J., Mangelsdorf, D.J., "Structural requirements of ligands for the oxysterol receptors LXR alpha and beta" Proceedings of the National Academy of Sciences, 96:266-271, January 1999
Peet, D.J., Turley, S.D., Ma, W., Janowski, B.A., Lobaccaro, J.A., Hammer, R.E., Mangelsdorf, D.J., "Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear receptor LXR alpha." Cell, 93:693-704, May 1998
Janowski, B.A., Willy, P.J., Rama Devi, T., Falck, J.R., Mangelsdorf, D.J., "Identification of a signaling pathway mediated by the nuclear receptor, LXR alpha." Nature, 383:728-731, October 1996
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