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Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism

BACKGROUND: Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this st...

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Autores principales: Pogue-Geile, Kay L, Chen, Ru, Bronner, Mary P, Crnogorac-Jurcevic, Tatjana, Moyes, Kara White, Dowen, Sally, Otey, Carol A, Crispin, David A, George, Ryan D, Whitcomb, David C, Brentnall, Teresa A
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751121/
https://www.ncbi.nlm.nih.gov/pubmed/17194196
http://dx.doi.org/10.1371/journal.pmed.0030516
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author Pogue-Geile, Kay L
Chen, Ru
Bronner, Mary P
Crnogorac-Jurcevic, Tatjana
Moyes, Kara White
Dowen, Sally
Otey, Carol A
Crispin, David A
George, Ryan D
Whitcomb, David C
Brentnall, Teresa A
author_facet Pogue-Geile, Kay L
Chen, Ru
Bronner, Mary P
Crnogorac-Jurcevic, Tatjana
Moyes, Kara White
Dowen, Sally
Otey, Carol A
Crispin, David A
George, Ryan D
Whitcomb, David C
Brentnall, Teresa A
author_sort Pogue-Geile, Kay L
collection PubMed
description BACKGROUND: Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. METHODS AND FINDINGS: A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. CONCLUSIONS: These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.
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spelling pubmed-17511212007-03-24 Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism Pogue-Geile, Kay L Chen, Ru Bronner, Mary P Crnogorac-Jurcevic, Tatjana Moyes, Kara White Dowen, Sally Otey, Carol A Crispin, David A George, Ryan D Whitcomb, David C Brentnall, Teresa A PLoS Med Research Article BACKGROUND: Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. METHODS AND FINDINGS: A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. CONCLUSIONS: These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities. Public Library of Science 2006-12 2006-12-12 /pmc/articles/PMC1751121/ /pubmed/17194196 http://dx.doi.org/10.1371/journal.pmed.0030516 Text en © 2006 Pogue-Geile et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pogue-Geile, Kay L
Chen, Ru
Bronner, Mary P
Crnogorac-Jurcevic, Tatjana
Moyes, Kara White
Dowen, Sally
Otey, Carol A
Crispin, David A
George, Ryan D
Whitcomb, David C
Brentnall, Teresa A
Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title_full Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title_fullStr Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title_full_unstemmed Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title_short Palladin Mutation Causes Familial Pancreatic Cancer and Suggests a New Cancer Mechanism
title_sort palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751121/
https://www.ncbi.nlm.nih.gov/pubmed/17194196
http://dx.doi.org/10.1371/journal.pmed.0030516
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