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scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs
BACKGROUND: Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760524/ https://www.ncbi.nlm.nih.gov/pubmed/19778415 http://dx.doi.org/10.1186/1741-7007-7-62 |
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author | Leong, Gregory R Goulding, Karen R Amin, Nancy Richardson, Helena E Brumby, Anthony M |
author_facet | Leong, Gregory R Goulding, Karen R Amin, Nancy Richardson, Helena E Brumby, Anthony M |
author_sort | Leong, Gregory R |
collection | PubMed |
description | BACKGROUND: Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations. RESULTS: We find that genetically distinct atypical protein kinase C (aPKC)-dependent and Jun N-terminal kinase (JNK)-dependent alterations in scrib mutants drive epithelial tumourigenesis. First, we show that over-expression of the apical cell polarity determinants Crumbs (Crb) or aPKC induces similar cell morphology defects and over-proliferation phenotypes as scrib loss-of-function. However, the morphological and proliferative defects in scrib mutants are independent of Crb function, and instead can be rescued by a dominant negative (kinase dead) aPKC transgene. Secondly, we demonstrate that loss of Scrib promotes oncogene-mediated transformation through both aPKC and JNK-dependent pathways. JNK normally promotes apoptosis of scrib mutant cells. However, in cooperation with oncogenic activated Ras or Notch signalling, JNK becomes an essential driver of tumour overgrowth and invasion. aPKC-dependent signalling in scrib mutants cooperates with JNK to significantly enhance oncogene-mediated tumour overgrowth. CONCLUSION: These results demonstrate distinct aPKC and JNK-dependent pathways through which loss of Scrib promotes tumourigenesis in Drosophila. This is likely to have a direct relevance to the way in which human Scrib can similarly restrain an oncogene-mediated transformation and, more generally, on how the outcome of oncogenic signalling can be profoundly perturbed by defects in apico-basal epithelial cell polarity. |
format | Text |
id | pubmed-2760524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-27605242009-10-13 scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs Leong, Gregory R Goulding, Karen R Amin, Nancy Richardson, Helena E Brumby, Anthony M BMC Biol Research Article BACKGROUND: Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations. RESULTS: We find that genetically distinct atypical protein kinase C (aPKC)-dependent and Jun N-terminal kinase (JNK)-dependent alterations in scrib mutants drive epithelial tumourigenesis. First, we show that over-expression of the apical cell polarity determinants Crumbs (Crb) or aPKC induces similar cell morphology defects and over-proliferation phenotypes as scrib loss-of-function. However, the morphological and proliferative defects in scrib mutants are independent of Crb function, and instead can be rescued by a dominant negative (kinase dead) aPKC transgene. Secondly, we demonstrate that loss of Scrib promotes oncogene-mediated transformation through both aPKC and JNK-dependent pathways. JNK normally promotes apoptosis of scrib mutant cells. However, in cooperation with oncogenic activated Ras or Notch signalling, JNK becomes an essential driver of tumour overgrowth and invasion. aPKC-dependent signalling in scrib mutants cooperates with JNK to significantly enhance oncogene-mediated tumour overgrowth. CONCLUSION: These results demonstrate distinct aPKC and JNK-dependent pathways through which loss of Scrib promotes tumourigenesis in Drosophila. This is likely to have a direct relevance to the way in which human Scrib can similarly restrain an oncogene-mediated transformation and, more generally, on how the outcome of oncogenic signalling can be profoundly perturbed by defects in apico-basal epithelial cell polarity. BioMed Central 2009-09-24 /pmc/articles/PMC2760524/ /pubmed/19778415 http://dx.doi.org/10.1186/1741-7007-7-62 Text en Copyright © 2009 Leong et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Leong, Gregory R Goulding, Karen R Amin, Nancy Richardson, Helena E Brumby, Anthony M scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title | scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title_full | scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title_fullStr | scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title_full_unstemmed | scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title_short | scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs |
title_sort | scribble mutants promote apkc and jnk-dependent epithelial neoplasia independently of crumbs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760524/ https://www.ncbi.nlm.nih.gov/pubmed/19778415 http://dx.doi.org/10.1186/1741-7007-7-62 |
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