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Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1.

Besemer, Juergen and Harant, Hanna and Wang, Shirley and Oberhauser, Berndt and Marquardt, Kathi and Foster, Carolyn-Ann and Schreiner, Erwin and De Vries, Jan Egbert and Dascher, Christiane and Lindley, Ivan-J.D. (2005) Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1. Nature, 436 (7048). pp. 290-293. ISSN 1476-4687

Abstract

Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention. We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum (ER), through a process that involves the translocon component Sec61beta. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 14 Dec 2009 13:57
Last Modified: 31 Jan 2013 01:13
URI: https://oak.novartis.com/id/eprint/565

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