Cargando…

Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells

BACKGROUND: Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-ca...

Descripción completa

Detalles Bibliográficos
Autores principales: Kenny, Paraic A, Enver, Tariq, Ashworth, Alan
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545969/
https://www.ncbi.nlm.nih.gov/pubmed/15642117
http://dx.doi.org/10.1186/1471-2407-5-3
_version_ 1782122226856755200
author Kenny, Paraic A
Enver, Tariq
Ashworth, Alan
author_facet Kenny, Paraic A
Enver, Tariq
Ashworth, Alan
author_sort Kenny, Paraic A
collection PubMed
description BACKGROUND: Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells. METHODS: Gene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of β-catenin was used to identify target genes of this pathway. RESULTS: The differential expression in response to ΔNβ-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/β-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon ΔNβ-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue. CONCLUSIONS: HIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer.
format Text
id pubmed-545969
institution National Center for Biotechnology Information
language English
publishDate 2005
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-5459692005-01-28 Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells Kenny, Paraic A Enver, Tariq Ashworth, Alan BMC Cancer Research Article BACKGROUND: Deregulation of the Wnt/ β-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in β-catenin stabilization and accumulation, and the aberrant modulation of β-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells. METHODS: Gene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of β-catenin was used to identify target genes of this pathway. RESULTS: The differential expression in response to ΔNβ-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/β-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon ΔNβ-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue. CONCLUSIONS: HIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer. BioMed Central 2005-01-10 /pmc/articles/PMC545969/ /pubmed/15642117 http://dx.doi.org/10.1186/1471-2407-5-3 Text en Copyright © 2005 Kenny et al; licensee BioMed Central Ltd.
spellingShingle Research Article
Kenny, Paraic A
Enver, Tariq
Ashworth, Alan
Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title_full Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title_fullStr Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title_full_unstemmed Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title_short Receptor and secreted targets of Wnt-1/β-catenin signalling in mouse mammary epithelial cells
title_sort receptor and secreted targets of wnt-1/β-catenin signalling in mouse mammary epithelial cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545969/
https://www.ncbi.nlm.nih.gov/pubmed/15642117
http://dx.doi.org/10.1186/1471-2407-5-3
work_keys_str_mv AT kennyparaica receptorandsecretedtargetsofwnt1bcateninsignallinginmousemammaryepithelialcells
AT envertariq receptorandsecretedtargetsofwnt1bcateninsignallinginmousemammaryepithelialcells
AT ashworthalan receptorandsecretedtargetsofwnt1bcateninsignallinginmousemammaryepithelialcells