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Beta-catenin cleavage enhances transcriptional activation.

Beta-catenin cleavage enhances transcriptional activation.
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Goretsky T, Bradford EM, Ye Q, Lamping OF, Vanagunas T, Moyer MP, Keller PC, Sinh P, Llovet JM, Gao T, She QB, Li L, Barrett TA,


Goretsky T, Bradford EM, Ye Q, Lamping OF, Vanagunas T, Moyer MP, Keller PC, Sinh P, Llovet JM, Gao T, She QB, Li L, Barrett TA, (click to view)

Goretsky T, Bradford EM, Ye Q, Lamping OF, Vanagunas T, Moyer MP, Keller PC, Sinh P, Llovet JM, Gao T, She QB, Li L, Barrett TA,

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Scientific reports 2018 01 128(1) 671 doi 10.1038/s41598-017-18421-8
Abstract

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

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