Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors

G. Manenti, G. Trincucci, A. Pettinicchio, E. Amendola, M. Scarfò, T. A. Dragani

Research output: Contribution to journalArticle

Abstract

The Pas1 locus is the major tumor modifier of lung tumorigenesis in mouse inbred strains. Of six genes contained in a conserved haplotype, three (Casc1, Kras and Ifltd1) have been proposed as Pas1 candidates, but mechanistic evidence is sparse. Herein, we examined urethane-induced lung tumorigenesis in a new mouse model developed by replacing the Kras gene with an Hras gene in the susceptible A/J-type Pas1 locus and crossing these mice with either C57BL/6J or A/J mice. Heterozygous mice carrying the Hras-replacement gene were more susceptible than wild-type mice to lung carcinogenesis, indicating that Hras replacement not only compensates for Kras functions, but is more active. Indeed, most lung tumors carried a Gln61Leu mutation in the Hras-replacement gene, whereas no mutations were observed in the endogenous Hras gene. Thus, the context of the Kras locus determined mutability of ras genes. In mice carrying the Hras-replacement gene, the mutation frequency affecting the wild-type Kras gene was much higher when this gene was located in the A/J type than in the C57BL/6J-type Pas1 locus (12 versus 0%, -log P=5.0). These findings identify cis-acting elements in the Pas1 locus as the functional components controlling genetic susceptibility to lung tumorigenesis by modulating mutability of the Kras gene.

Original languageEnglish
Pages (from-to)5753-5758
Number of pages6
JournalOncogene
Volume27
Issue number43
DOIs
Publication statusPublished - Sep 25 2008

Keywords

  • Genetic susceptibility
  • Heredity
  • Lung cancer
  • Mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Fingerprint Dive into the research topics of 'Cis-acting genomic elements of the Pas1 locus control Kras mutability in lung tumors'. Together they form a unique fingerprint.

  • Cite this