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Beta-catenin cleavage enhances transcriptional activation.


ABSTRACT: Nuclear activation of Wnt/?-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that ?-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of ?-catenin phosphorylated at serine 552 (p?-Cat552). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) p?-Cat552, increased to the exclusion of full size (FS) forms of ?-catenin. LMW ?-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW p?-Cat552 in the nucleus of inflamed and cancerous cells. Nuclear chromatin bound localization of LMW p?-Cat552 was blocked in cells by inhibition of proteasomal chymotrypsin-like activity but not by other protease inhibitors. K48 polyubiquitinated FS and LMW ?-catenin were increased by treatment with bortezomib. Overexpressed in vitro double truncated ?-catenin increased transcriptional activity, cell proliferation and growth of tumor xenografts compared to FS ?-catenin. Serine 552-> alanin substitution abrogated K48 polyubiquitination,  ?-catenin nuclear translocation and tumor xenograft growth. These data suggest that a novel proteasome-dependent posttranslational modification of ?-catenin enhances transcriptional activation. Discovery of this pathway may be helpful in the development of diagnostic and therapeutic tools in colitis and cancer.

SUBMITTER: Goretsky T 

PROVIDER: S-EPMC5766502 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat<sup>552</sup>). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat<sup>552</sup>, increased to the exclusion of full size (FS) forms  ...[more]

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