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Biotech / Medical : ARIAD Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: squetch who wrote (210)	12/13/1997 4:11:00 PM
From: Miljenko Zuanic	Respond to of 4474

Few more details on gene expression/control mechanism: Full text: pnas.org Abstract: Proc. Natl. Acad. Sci. USA Vol. 94, pp. 10618-10623, September 1997 Biochemistry A versatile synthetic dimerizer for the regulation of protein-protein interactions Jane F. Amara, Tim Clackson, Victor M. Rivera, Tao Guo, Terence Keenan, Sridaran Natesan, Roy Pollock, Wu Yang, Nancy L. Courage, Dennis A. Holt, and Michael Gilman ARIAD Gene Therapeutics, Inc., 26 Landsdowne Street, Cambridge, MA 02139 Edited by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, and approved July 31, 1997 (received for review June 20, 1997) The use of low molecular weight organic compounds to induce dimerization or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies. Chemically induced dimerization can be used to activate intracellular signal transduction pathways or to control the activity of a bipartite transcription factor. Dimerizer systems based on the natural products cyclosporin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthetic, cell-permeable dimerizers composed of ligands for human FKBP12. These molecules have significantly reduced complexity and greater adaptability than natural product dimers. We report here the efficacies of several of these new synthetic compounds in regulating two types of protein dimerization events inside engineered cells-induction of apoptosis through dimerization of engineered Fas proteins and regulation of transcription through dimerization of transcription factor fusion proteins. One dimerizer in particular, AP1510, proved to be exceptionally potent and versatile in all experimental contexts tested.