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

Departments of ¹ Biomedical Sciences and ² Molecular Biology and Genetics, Cornell University, Ithaca, New York and ³ Rodent Histopathology Core, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Robert S. Weiss, Department of Biomedical Sciences, Cornell University, T2006C Veterinary Research Tower, Ithaca, NY 14853. Phone: 607-253-4443; Fax: 607-253-4212; E-mail: rsw26{at}cornell.edu.

Key Words: ribonucleotide reductase • lung cancer • mutagenesis • mismatch repair • K-ras

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]