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English

Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling

Contributors

Lin-Marq, Nathalie; Borel, Christelle; Antonarakis, Stylianos

Published in

Molecular genetics and genomics, vol. 273, no. 2, p. 184-196

Collection

  • Open Access - Licence nationale Springer

Publication date

2005

Abstract

Peutz-Jeghers syndrome (PJS) is caused by germline mutations in the LKB1 gene, which encodes a serine-threonine kinase that regulates cell proliferation and polarity. This autosomal dominant disorder is characterized by mucocutaneous melanin pigmentation, multiple gastrointestinal hamartomatous polyposis and an increased risk of developing various neoplasms. To understand the molecular pathogenesis of PJS phenotypes, we used microarrays to analyze gene expression profiles in proliferating HeLa cells transduced with lentiviral vectors expressing wild type or mutant LKB1 proteins. We show that gene expression is differentially affected by mutations that impair the kinase activity (K78I) or alter the cellular localization of the LKB1 protein. However, both mutations abrogate the ability of LKB1 to up-regulate the transcription of several genes involved in Wnt signaling, including DKK3, WNT5B and FZD2. In addition-and in contrast to the wild type protein-these LKB1 mutants fail to activate the GSK-3beta kinase, which otherwise phosphorylates beta-catenin. The increase in beta-catenin phosphorylation that occurs upon expression of wild-type LKB1 results in transcriptional inhibition of a canonical Wnt reporter gene. This suggests that pathogenic LKB1 mutations that lead to activation of the Wnt/beta-catenin pathway could contribute to the cancer predisposition of PJS patients.

Keywords

  • Cytoskeletal Proteins/metabolism
  • Flow Cytometry
  • Gene Expression Regulation
  • Genetic Vectors
  • Glycogen Synthase Kinase 3/ metabolism
  • Hela Cells
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins/ metabolism
  • Lentivirus
  • Luciferases/metabolism
  • Mutation/genetics
  • Oligonucleotide Array Sequence Analysis
  • Peutz-Jeghers Syndrome/ genetics/metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases/genetics/ metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/ physiology
  • Trans-Activators/metabolism
  • Transfection
  • Wnt Proteins
  • Beta Catenin

UNIGE affiliation entities

Citation (ISO format)

LIN-MARQ, Nathalie, BOREL, Christelle, ANTONARAKIS, Stylianos. Peutz-Jeghers LKB1 mutants fail to activate GSK-3beta, preventing it from inhibiting Wnt signaling. In: Molecular genetics and genomics, 2005, vol. 273, n° 2, p. 184–196. doi: 10.1007/s00438-005-1124-y

Main files (1)

Article (Published version)

Identifiers

Additional URL for this publication

http://www.springerlink.com/content/7egamjlt3aqy921m/fulltext.pdf

Journal ISSN

1617-4623
618views
513downloads

Technical informations

Creation

12/07/2010 11:58:44

First validation

12/07/2010 11:58:44

Update

14/03/2023 15:51:43

Status update

14/03/2023 15:51:43

Last indexation

29/10/2024 15:52:59
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