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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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Beta-catenin cleavage enhances transcriptional activation.

Goretsky Tatiana T Bradford Emily M EM Ye Qing Q Lamping Olivia F OF Vanagunas Tomas T Moyer Mary Pat MP Keller Patrick C PC Sinh Preetika P Llovet Josep M JM Gao Tianyan T She Qing-Bai QB Li Linheng L Barrett Terrence A TA

Scientific reports 20180112 1

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]

PMID: 29330435

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Project description:BackgroundThe urgent problem in the treatment of breast cancer is the recurrence induced by breast cancer stem cells (CSCs). Understanding the role and molecular mechanism of specific molecules in breast cancer stem cells can provide a theoretical basis for better treatment. TRIP6 is an adapter protein which belongs to the zyxin family of LIM proteins and is important in regulating the functions of CSCs. The present study aims to investigate the effects and mechanism of TRIP6 in breast cancer.MethodsTRIP6 expression in breast cancer cells and tissues were detected by Real-Time PCR, western blot and immunohistochemistry (IHC). MTT assays, colony formation assays, Xenografted tumor model and mammosphere formation assays were performed to investigate the oncogenic functions of TRIP6 in the tumorigenic capability and the tumor-initiating cell-like phenotype of breast cancer cells in vitro and in vivo. Luciferase reporter, subcellular fractionation and immunofluorescence staining assays were performed to determine the underlying mechanism of TRIP6-mediated stemness of breast cancer cells.ResultsTRIP6 expression was significantly upregulated in breast cancer, and was closely related to the clinicopathologic characteristics, poor overall survival (OS), relapse-free survival (RFS) and poor prognosis of breast cancer patients. Functional studies revealed that overexpression of TRIP6 significantly enhanced proliferative, tumorigenicity capability and the cancer stem cell-like properties of breast cancer in vitro and in vivo. On the contrary, silencing TRIP6 achieved the opposite results. Notably, we found that TRIP6 promoted Wnt/β-catenin signaling pathway in breast cancer to strengthen the tumor-initiating cell-like phenotype of breast cancer cells.ConclusionsThis study indicates that TRIP6 plays an important role in maintaining the stem cell-like characteristics of breast cancer cells, supporting the significance of TRIP6 as a novel potential prognostic biomarker and therapeutic target for diagnosis and treatment of breast cancer.

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Beta-catenin cleavage enhances transcriptional activation.

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Beta-catenin cleavage enhances transcriptional activation.

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