Cited by 16Protein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase SignalingNeurofibromatosis and Schwannoma Cases

K‐RasV14I‐induced Noonan syndrome predisposes to tumour development in mice

Hernández‐Porras, Isabel, Schuhmacher, Alberto J, Garcia‐Medina, Raquel, Jiménez, Beatriz, Cañamero, Marta, de Martino, Alba, Guerra, Carmen·2016·The Journal of Pathology

Abstract

The Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. A significant proportion of NS patients may also develop myeloproliferative disorders (MPDs), including juvenile myelomonocytic leukaemia (JMML). Surprisingly, scarce information is available in relation to other tumour types in these patients. We have previously developed and characterized a knock-in mouse model that carries one of the most frequent KRAS-NS-related mutations, the K-Ras(V14I) substitution, which recapitulates most of the alterations described in NS patients, including MPDs. The K-Ras(V14I) mutation is a mild activating K-Ras protein; thus, we have used this model to study tumour susceptibility in comparison with mice expressing the classical K-Ras(G12V) oncogene. Interestingly, our studies have shown that these mice display a generalized tumour predisposition and not just MPDs. In fact, we have observed that the K-Ras(V14I) mutation is capable of cooperating with the p16Ink4a/p19Arf and Trp53 tumour suppressors, as well as with other risk factors such as pancreatitis, thereby leading to a higher cancer incidence. In conclusion, our results illustrate that the K-Ras(V14I) activating protein is able to induce cancer, although at a much lower level than the classical K-Ras(G12V) oncogene, and that it can be significantly modulated by both genetic and non-genetic events. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Crossref · 10.1002/path.4719

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Authors
Hernández‐Porras, I., Schuhmacher, A. J., Garcia‐Medina, R., Jiménez, B., Cañamero, M., de Martino, A., & Guerra, C.
Affiliations
  • Molecular Oncology Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid Spain
  • Spanish National Cancer Research Centre (ES)
  • Biotechnology Programs Centro Nacional de Investigaciones Oncológicas (CNIO) Madrid Spain
Corresponding author
Guerra, Carmen
Venue
The Journal of Pathology
Publisher
Wiley
Published
2016-04-26
Volume
239
Issue
2
Pages
206-217
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
OpenAlex
W2312134491
Cited by
16
References
52
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2019: 1 · 2018: 2 · 2017: 2
FWCI
0.87
Type
journal article
Language
en
Open access
closed
Locations
  • The Journal of Pathology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Fundación Ramón Areces (FRA 01‐09‐001)
  • Instituto de Salud Carlos III
  • Fundación BBVA
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
Keywords
Noonan syndrome, cancer susceptibility, juvenile myelomonocytic leukemia, myeloproliferative neoplasms, KRAS G12V, Trp53, pancreatitis, knock-in mice
MeSH terms
Alleles, Animals, Disease Models, Animal, Disease Susceptibility, Female, Heart Defects, Congenital, Genetic Carrier Screening, Humans, Lung Neoplasms, Male, Mice, Inbred C57BL, Mutation, Neoplasms, Noonan Syndrome, Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Amino Acid Substitution, Mice

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