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Beta-catenin cleavage enhances transcriptional activation Goretsky, Tatiana Bradford, Emily M. Ye, Qing Lamping, Olivia F. Vanagunas, Tomas Moyer, Mary Pat Keller, Patrick C. Sinh, Preetika Llovet i Bayer, Josep Maria Gao, Tianyan She, Qing-Bai Li, Linheng Barrett, Terrence A. Colitis Càncer colorectal Inflamació Colitis Colorectal cancer Inflammation 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. 2018-11-28T11:24:44Z 2018-11-28T11:24:44Z 2018-01-12 2018-11-28T11:24:45Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/s41598-017-18421-8 Scientific Reports, 2018, vol. 8, num. 1, p. 671 https://doi.org/10.1038/s41598-017-18421-8 cc-by (c) Goretsky, Tatiana et al., 2018 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess Nature Publishing Group Articles publicats en revistes (Medicina)