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HERO ID
1600910
Reference Type
Journal Article
Title
Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis
Author(s)
To, MD; Rosario, RD; Westcott, PMK; Banta, KL; Balmain, A
Year
2013
Is Peer Reviewed?
1
Journal
Oncogene
ISSN:
0950-9232
EISSN:
1476-5594
Volume
32
Issue
34
Page Numbers
4028-4033
Language
English
PMID
22945650
DOI
10.1038/onc.2012.404
Web of Science Id
WOS:000323748100011
Abstract
Ras oncogenes (Hras, Kras and Nras) are important drivers of carcinogenesis. However, tumors with Ras mutations often show loss of the corresponding wild-type (WT) allele, suggesting that proto-oncogenic forms of Ras can function as a suppressor of carcinogenesis. In vitro studies also suggest that WT Ras proteins can suppress the tumorigenic properties of alternate mutant Ras family members, but in vivo evidence for these heterologous interactions is lacking. We have investigated the genetic interactions between different combinations of mutant and WT Ras alleles in vivo using carcinogen-induced lung and skin carcinogenesis in mice with targeted deletion of different Ras family members. The major suppressor effect of WT Kras is observed only in mutant Kras-driven lung carcinogenesis, where loss of one Kras allele led to increased tumor number and size. Deletion of one Hras allele dramatically reduced the number of skin papillomas with Hras mutations, consistent with Hras as the major target of mutation in these tumors. However, skin carcinoma numbers were very similar, suggesting that WT Hras functions as a suppressor of progression from papillomas to invasive squamous carcinomas. In the skin, the Kras proto-oncogene functions cooperatively with mutant Hras to promote papilloma development, although the effect is relatively small. In contrast, the Hras proto-oncogene attenuated the activity of mutant Kras in lung carcinogenesis. Interestingly, loss of Nras increased the number of mutant Kras-induced lung tumors, but decreased the number of mutant Hras-induced skin papillomas. These results show that the strongest suppressor effects of WT Ras are only seen in the context of mutation of the cognate Ras protein, and only relatively weak effects are detected on tumor development induced by mutations in alternative family members. The data also underscore the complex and context-dependent nature of interactions between proto-oncogenic and oncogenic forms of different Ras family members during tumor development.
Keywords
Ras protein; carcinogen; oncogene ras; skin carcinogenesis; wild type; mutation; neoplasm; papilloma; carcinogenesis; lung carcinogenesis; skin papilloma; proto oncogene; skin carcinoma; lung tumor; squamous cell carcinoma; gene interaction; in vitro study
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Mouse Lung Tumor Workshop 2014
Cited
Session 4 – Cellular & Subcellular Events
Molecular toxicology
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