Rigel Team Discovers New Regulators of the Immune System
Monday September 15, 7:30 am ET
LONDON and SOUTH SAN FRANCISCO, Calif., Sept. 15 /PRNewswire-FirstCall/ -- In an attempt to find new regulators of the immune system, a team of researchers at Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL - News) have created a successful method for discovering targets that are involved in signaling pathways. As published this week in the Journal of Biology, the team conducted a functional genome-wide screen and discovered novel modulators of T-cell receptor signaling that could aid in the development of drugs that target the immune response.
T-cells are an integral part of the immune response. Helper T-cells encourage antibody-producing B-cells to replicate and secrete antibodies, and play a role in the inflammatory response. Cytotoxic T-cells identify and kill cells that have been infected with viruses. As all these functions are initiated by T-cell receptors, each response must be determined by the particular set of downstream signaling components that are activated. Until now, identification of novel components in these pathways has been slow and time-consuming. As the article notes, the researchers believe that this study demonstrates, "a successful approach for discovering and validating, in a functionally relevant context, important immune regulators on a genome-wide scale." The research team, led by Dr. Charlene Liao, as part of a collaboration with Novartis, used retroviruses to carry into cells lymphoid genes that regulate T-cell receptor signaling when expressed. Normally, a cell surface marker called CD69 is up-regulated when T-cell receptors are activated. However, the researchers selected cells that, when given a new gene to express, failed to upregulate this protein. They then checked that this repression was caused by the introduced gene and was not a side effect of the procedure. After three rounds of selection, 33 individual genes were cloned. Some of these were already known to play a role in the immune response, some had previously had unrelated functions assigned to them, and others were completely novel.
The Rigel team carried out additional experiments on three of the genes that were identified in the screen to verify their functional relevance. These experiments confirmed that the genes EDG1, PAK2, and the previously unidentified TRAC-1 were normally expressed in the lymphoid system and that truncated versions of their proteins could repress T-cell receptor signaling in T-cells.
The authors write: "This approach provides a tool for functional cloning of regulators in numerous signal transduction pathways. (...) Importantly, the outlined strategy, which requires no prior sequence information of the players involved, does not bias the search to previously known signaling molecules, molecules flagged by DNA-array technologies or signaling molecules discovered in other contexts."
Once published, this article will be freely available online, in keeping with BioMed Central's policy of open access to research articles:
Systematic Identification of Regulator Proteins Critical for T Cell activation
Peter Chu, Jorge Pardo, Haoran Zhao, Connie C Li, Erlina Pali, Mary M Shen, Kunbin Qu, Simon X Yu, Betty C B Huang, Peiwen Yu, Esteban S Masuda, Frank Kolbinger, Gregorio Aversa, Jan de Vries, Donald G Payan and X Charlene Liao.
Journal of Biology 2:21
jbiol.com
Published 15th September 2003
Prior to publication this article will be available to the press at: jbiol.com
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Contact Dr. Donald G. Payan Rigel's CSO and Executive Vice President (dgpayan@rigel.com) for further information about this research.
Alternatively contact Gemma Bradley by email at press@biomedcentral.com or by phone on +44-0-20-7323-0323.
Journal of Biology (http://jbiol.com) is published by BioMed Central ( biomedcentral.com ), an independent online publishing house committed to providing immediate free access to peer-reviewed biological and medical research. This commitment is based on the view that open access to research is essential to the rapid and efficient communication of science. In addition to open-access original research, BioMed Central also publishes reviews and other subscription-based content.
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