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 beta-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 beta-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.

• Authors: Mariana Brocardo, Ying Lei, Anthony Tighe, Stephen S Taylor, Myth T S Mok, Beric R Henderson
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 9 Pg. 5950-9 (Feb 29 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18160396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenomatous Polyposis Coli Protein
• BAX protein, human
• BCL2L1 protein, human
• BIRC5 protein, human
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Survivin
• bcl-2-Associated X Protein
• bcl-X Protein
• beta Catenin

Topics

• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Amino Acid Sequence (genetics)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (genetics)
• Chromosome Segregation (genetics)
• Colonic Neoplasms (genetics, metabolism)
• Humans
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins (genetics, metabolism)
• Microtubules (genetics, metabolism)
• Mitochondria (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Sequence Deletion (genetics)
• Survivin
• bcl-2-Associated X Protein (genetics, metabolism)
• bcl-X Protein (genetics, metabolism)
• beta Catenin (genetics, metabolism)