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Sci Rep. 2018 Jan 12;8(1):671. doi: 10.1038/s41598-017-18421-8.

Beta-catenin cleavage enhances transcriptional activation.

Author information

1
Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, KY, USA.
2
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
3
Louisiana State University Health Sciences Center, New Orleans, LA, USA.
4
INCELL Corporation, San Antonio, TX, USA.
5
Northwestern University, Chicago, IL, USA.
6
The Mount Sinai Hospital, New York, NY, USA.
7
Stowers Institute for Medical Research, Kansas City, MO, USA.
8
Dept of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
9
Department of Internal Medicine, Division of Gastroenterology, University of Kentucky, Lexington, KY, USA. t.barrett@uky.edu.

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.

PMID:
29330435
PMCID:
PMC5766502
DOI:
10.1038/s41598-017-18421-8
[Indexed for MEDLINE]
Free PMC Article

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