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Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism

Pogue-Geile, KL and Chen, R and Bronner, MP and Crnogorac-Jurcevic, T and Moyes, KW and Dowen, S and Otey, CA and Crispin, DA and George, RD and Whitcomb, DC and Brentnall, TA (2006) Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Medicine, 3 (12). 2216 - 2228. ISSN 1549-1277

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Abstract

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. © 2006 Pogue-Geile et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pogue-Geile, KL
Chen, R
Bronner, MP
Crnogorac-Jurcevic, T
Moyes, KW
Dowen, S
Otey, CA
Crispin, DA
George, RD
Whitcomb, DCwhitcomb@pitt.eduWHITCOMB
Brentnall, TA
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorTuveson, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 December 2006
Date Type: Publication
Journal or Publication Title: PLoS Medicine
Volume: 3
Number: 12
Page Range: 2216 - 2228
DOI or Unique Handle: 10.1371/journal.pmed.0030516
Schools and Programs: School of Medicine > Cell Biology and Molecular Physiology
Refereed: Yes
ISSN: 1549-1277
PubMed ID: 17194196
Date Deposited: 11 Jul 2012 17:28
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/12855

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