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 Tighe, Stephen S. Taylor, Myth T S Mok, Beric R. Henderson

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages5950-5959
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number9
DOIs
Publication statusPublished - 29 Feb 2008
Externally publishedYes

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Adenomatous Polyposis Coli Protein
Adenomatous Polyposis Coli
Mitochondria
Tumors
Cell Survival
Cells
Mutation
beta Catenin
Neoplasms
Peptides
Confocal microscopy
Chromosomes
Fractionation
Genes
Apoptosis
Membranes
APC Genes
Proteins
Chromosome Segregation
Sequence Deletion

Cite this

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title = "Mitochondrial targeting of adenomatous polyposis coli protein is stimulated by truncating cancer mutations: Regulation of Bcl-2 and implications for cell survival",
abstract = "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.",
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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. / Brocardo, Mariana; Lei, Ying; Tighe, Anthony; Taylor, Stephen S.; Mok, Myth T S; Henderson, Beric R.

In: Journal of Biological Chemistry, Vol. 283, No. 9, 29.02.2008, p. 5950-5959.

Research output: Contribution to journalArticleResearchpeer-review

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