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Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer

Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enh...

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Autores principales: Weyandt, Jamie D., Lampson, Benjamin L., Tang, Sherry, Mastrodomenico, Matthew, Cardona, Diana M., Counter, Christopher M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599940/
https://www.ncbi.nlm.nih.gov/pubmed/26452271
http://dx.doi.org/10.1371/journal.pone.0140253
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author Weyandt, Jamie D.
Lampson, Benjamin L.
Tang, Sherry
Mastrodomenico, Matthew
Cardona, Diana M.
Counter, Christopher M.
author_facet Weyandt, Jamie D.
Lampson, Benjamin L.
Tang, Sherry
Mastrodomenico, Matthew
Cardona, Diana M.
Counter, Christopher M.
author_sort Weyandt, Jamie D.
collection PubMed
description Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of Hras increases tumor load and reduces survival in an oncogenic Kras-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type Hras may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of Hras are nullified in a homozygous mutant p53 background. As such, loss of wild-type Hras fosters the earliest stages of pancreatic cancer in a p53-dependent manner.
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spelling pubmed-45999402015-10-20 Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer Weyandt, Jamie D. Lampson, Benjamin L. Tang, Sherry Mastrodomenico, Matthew Cardona, Diana M. Counter, Christopher M. PLoS One Research Article Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and Hras, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of Hras increases tumor load and reduces survival in an oncogenic Kras-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type Hras may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of Hras are nullified in a homozygous mutant p53 background. As such, loss of wild-type Hras fosters the earliest stages of pancreatic cancer in a p53-dependent manner. Public Library of Science 2015-10-09 /pmc/articles/PMC4599940/ /pubmed/26452271 http://dx.doi.org/10.1371/journal.pone.0140253 Text en © 2015 Weyandt 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
Weyandt, Jamie D.
Lampson, Benjamin L.
Tang, Sherry
Mastrodomenico, Matthew
Cardona, Diana M.
Counter, Christopher M.
Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title_full Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title_fullStr Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title_full_unstemmed Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title_short Wild-Type Hras Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer
title_sort wild-type hras suppresses the earliest stages of tumorigenesis in a genetically engineered mouse model of pancreatic cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599940/
https://www.ncbi.nlm.nih.gov/pubmed/26452271
http://dx.doi.org/10.1371/journal.pone.0140253
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