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Mutat Res. 2005 Dec 11;591(1-2):161-72. Epub 2005 Jul 27.

Lysosomal trafficking of beta-catenin induced by the tea polyphenol epigallocatechin-3-gallate.

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1
Linus Pauling Institute, 571 Weniger Hall, Oregon State University, Corvallis, OR 97331-6512, USA.

Abstract

beta-Catenin is a cadherin-binding protein involved in cell-cell adhesion, which also functions as a transcriptional activator when complexed in the nucleus with members of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family of proteins. There is considerable interest in mechanisms that down-regulate beta-catenin, since this provides an avenue for the prevention of colorectal and other cancers in which beta-catenin is frequently over-expressed. We show here that physiologically relevant concentrations of the tea polyphenol epigallocatechin-3-gallate (EGCG) inhibited beta-catenin/TCF-dependent reporter activity in human embryonic kidney 293 cells transfected with wild type or mutant beta-catenins, and there was a corresponding decrease in beta-catenin protein levels in the nuclear, cytosolic and membrane-associated fractions. However, beta-catenin accumulated as punctate aggregates in response to EGCG treatment, including in human colon cancer cells over-expressing beta-catenin endogenously. Confocal microscopy studies revealed that the aggregated beta-catenin in HEK293 cells was extra-nuclear and co-localized with lysosomes, suggesting that EGCG activated a pathway involving lysosomal trafficking of beta-catenin. Lysosomal inhibitors leupeptin and transepoxysuccinyl-l-leucylamido(4-guanido)butane produced an increase in beta-catenin protein in total cell lysates, without a concomitant increase in beta-catenin transcriptional activity. These data provide the first evidence that EGCG facilitates the trafficking of beta-catenin into lysosomes, presumably as a mechanism for sequestering beta-catenin and circumventing further nuclear transport and activation of beta-catenin/TCF/LEF signaling.

PMID:
16054165
PMCID:
PMC2276571
DOI:
10.1016/j.mrfmmm.2005.03.029
[Indexed for MEDLINE]
Free PMC Article

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