Data from Broad Overexpression of Ribonucleotide Reductase Genes in Mice Specifically Induces Lung Neoplasms

Authors:
  • XXXia Xu
    Xia Xu
  • JPJennifer L. Page
    Jennifer L. Page
  • JSJennifer A. Surtees
    Jennifer A. Surtees
  • HLHouchun Liu
    Houchun Liu
  • SLSarah Lagedrost
    Sarah Lagedrost
  • YLYoung Lu
    Young Lu
  • RBRoderick Bronson
    Roderick Bronson
  • EAEric Alani
    Eric Alani
  • ANAlexander Yu. Nikitin
    Alexander Yu. Nikitin
  • RWRobert S. Weiss
    Robert S. Weiss
Open Access
Publisher website
Google Scholar
Abstract
Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in nucleotide biosynthesis and plays a central role in genome maintenance. Although a number of regulatory mechanisms govern RNR activity, the physiologic effect of RNR deregulation had not previously been examined in an animal model. We show here that overexpression of the small RNR subunit potently and selectively induces lung neoplasms in transgenic mice and is mutagenic in cultured cells. Combining RNR deregulation with defects in DNA mismatch repair, the cellular mutation correction system, synergistically increased RNR-induced mutagenesis and carcinogenesis. Moreover, the proto-oncogene K-ras was identified as a frequent mutational target in RNR-induced lung neoplasms. Together, these results show that RNR deregulation promotes lung carcinogenesis through a mutagenic mechanism and establish a new oncogenic activity for a key regulator of nucleotide metabolism. Importantly, RNR-induced lung neoplasms histopathologically resemble human papillary adenocarcinomas and arise stochastically via a mutagenic mechanism, making RNR transgenic mice a valuable model for lung cancer. [Cancer Res 2008;68(8):2652–60]