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J. Biol. Chem., Vol. 283, Issue 9, 5950-5959, February 29, 2008

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Mitochondrial Targeting of Adenomatous Polyposis Coli Protein Is Stimulated by Truncating Cancer Mutations

REGULATION OF Bcl-2 AND IMPLICATIONS FOR CELL SURVIVAL^*

Mariana Brocardo, Ying Lei, Anthony Tighe¹, Stephen S. Taylor², Myth T. S. Mok, and Beric R. Henderson³

From the Westmead Institute for Cancer Research, University of Sydney, Westmead Millennium Institute at Westmead Hospital, Westmead, New South Wales 2145, Australia and the Faculty of Life Sciences, University of Manchester, Manchester M139PT, United Kingdom

The adenomatous polyposis coli (APC) protein tumor suppressor is mutated in the majority of colon cancers. Most APC gene mutations cause deletion of the C terminus and disrupt APC regulation of β-catenin turnover, microtubule dynamics, and chromosome segregation. Truncated APC mutant peptides may also gain unique properties, not exhibited by wild-type APC, which contribute to tumor cell survival and proliferation. Here we report a differential subcellular localization pattern for wild-type and mutant APC. A pool of APC truncation mutants was detected at mitochondria by cellular fractionation and confocal microscopy. In contrast, wild-type APC located poorly at mitochondria. Similar results were observed for endogenous and stably induced forms of APC, with the shortest N-terminal mutant peptides (N750, N853, N1309, N1337) displaying the strongest mitochondrial staining. The knock down of mutant APC(N1337) in SW480 tumor cells caused an increase in apoptosis and mitochondrial membrane permeability, and this correlated with reduced Bcl-2 protein levels in mitochondrial fractions. Interestingly, the silencing of APC did not alter expression of β-catenin or the apoptotic regulatory factors Bax, Bcl-xL, or survivin. APC formed a complex with Bcl-2 in mitochondrial fractions, and this may contribute to the APC-dependent regulation of Bcl-2. We propose that a subset of cancer mutations induce APC mitochondrial localization and that APC regulation of Bcl-2 at mitochondria may contribute to tumor cell survival.

Received for publication, October 24, 2007 , and in revised form, December 22, 2007.

^* This work was supported by a grant (to B. R. H.) from the Australian Research Council and the National Health and Medical Research Council of Australia. 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-S5.

¹ Supported by the AICR.

² A Cancer Research UK Senior Fellow.

³ A Senior Research Fellow of the National Health and Medical Research Council of Australia. To whom correspondence should be addressed: Westmead Millennium Inst., Darcy Rd. (PO Box 412), Westmead, NSW 2145, Australia. Tel.: 61-2-9845-9057; Fax: 61-2-9845-9102; E-mail: beric_henderson{at}wmi.usyd.edu.au.

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