HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 14, 8961-8968, April 4, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/14/8961    most recent M709525200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sekine, K. Articles by Naito, M. PubMed PubMed Citation Articles by Sekine, K. Articles by Naito, M. Social Bookmarking                      What's this?

Small Molecules Destabilize cIAP1 by Activating Auto-ubiquitylation^*

Keiko Sekine, Kohei Takubo, Ryo Kikuchi, Michie Nishimoto, Masayuki Kitagawa, Fuminori Abe, Kiyohiro Nishikawa, Takashi Tsuruo^¶, and Mikihiko Naito¹

From the Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Pharmaceutical Research Laboratories, Research & Development Group, Nippon Kayaku Co., Ltd, 3-31-12 Shimo, Kita-ku, Tokyo 115-8588, and ^¶Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan

Overexpression of an anti-apoptotic protein cIAP1 caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, which confers resistance to chemotherapy and radiotherapy. Here we report cIAP1 to be selectively down-regulated by a class of small molecules ((–)-N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl]-L-leucine methyl ester (ME-BS)), resulting in a sensitization of cancer cells to apoptosis. ME-BS directly interacts with the BIR3 domain of cIAP1, promotes auto-ubiquitylation dependent on its RING domain, and facilitates proteasomal degradation of cIAP1. Other IAPs such as XIAP and cIAP2 were not affected by ME-BS. These results suggest targeted destabilization of cIAP1 by small molecules as a novel method to treat cancers expressing cIAP1, which interferes with treatment. Manipulation of the intrinsic ubiquitinligase activity could be a novel strategy to develop small molecules for therapeutic purposes.

Received for publication, November 20, 2007 , and in revised form, January 29, 2008.

^* This work was supported by Ministry of Education, Science, Sports and Culture, Japan Grants-in Aid for Cancer Research and Scientific Research and by the Pharmacological Research Foundation, Tokyo. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S9.

¹ To whom correspondence should be addressed. Fax: 81-3-5841-8487; E-mail: mnaito{at}iam.u-tokyo.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?