Beta-catenin cleavage enhances transcriptional activation

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)...

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Autores: 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.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/126538
Acceso en línea:https://hdl.handle.net/2445/126538
Access Level:acceso abierto
Palabra clave:Colitis
Càncer colorectal
Inflamació
Colorectal cancer
Inflammation
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repository_id_str
spelling Beta-catenin cleavage enhances transcriptional activationGoretsky, TatianaBradford, Emily M.Ye, QingLamping, Olivia F.Vanagunas, TomasMoyer, Mary PatKeller, Patrick C.Sinh, PreetikaLlovet i Bayer, Josep MariaGao, TianyanShe, Qing-BaiLi, LinhengBarrett, Terrence A.ColitisCàncer colorectalInflamacióColitisColorectal cancerInflammationNuclear 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.Nature Publishing Group2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/126538Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/s41598-017-18421-8Scientific Reports, 2018, vol. 8, num. 1, p. 671https://doi.org/10.1038/s41598-017-18421-8cc-by (c) Goretsky, Tatiana et al., 2018http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1265382026-05-27T06:46:51Z
dc.title.none.fl_str_mv Beta-catenin cleavage enhances transcriptional activation
title Beta-catenin cleavage enhances transcriptional activation
spellingShingle Beta-catenin cleavage enhances transcriptional activation
Goretsky, Tatiana
Colitis
Càncer colorectal
Inflamació
Colitis
Colorectal cancer
Inflammation
title_short Beta-catenin cleavage enhances transcriptional activation
title_full Beta-catenin cleavage enhances transcriptional activation
title_fullStr Beta-catenin cleavage enhances transcriptional activation
title_full_unstemmed Beta-catenin cleavage enhances transcriptional activation
title_sort Beta-catenin cleavage enhances transcriptional activation
dc.creator.none.fl_str_mv 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.
author Goretsky, Tatiana
author_facet 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.
author_role author
author2 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.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Colitis
Càncer colorectal
Inflamació
Colitis
Colorectal cancer
Inflammation
topic Colitis
Càncer colorectal
Inflamació
Colitis
Colorectal cancer
Inflammation
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/126538
url https://hdl.handle.net/2445/126538
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv 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
dc.rights.none.fl_str_mv cc-by (c) Goretsky, Tatiana et al., 2018
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Goretsky, Tatiana et al., 2018
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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