Journal
CANCER RESEARCH
Volume 68, Issue 8, Pages 2652-2660Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-5873
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Funding
- NCI NIH HHS [R01 CA108773, R56 CA096823, R01 CA096823, CA96823, R01 CA108773-04, R01 CA096823-05] Funding Source: Medline
- NCRR NIH HHS [K26 RR017595, RR017595, K26 RR017595-05] Funding Source: Medline
- NIGMS NIH HHS [R01 GM053085, R01 GM053085-13, T32GM07617, GM53085, T32 GM007273, T32 GM007273-33, T32 GM007617] Funding Source: Medline
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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.
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