Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms.
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.
Xu
Xia
X
Department of Biomedical Sciences, Cornell University, Ithaca, New York 14853, USA.
Page
Jennifer L
JL
Surtees
Jennifer A
JA
Liu
Houchun
H
Lagedrost
Sarah
S
Lu
Young
Y
Bronson
Roderick
R
Alani
Eric
E
Nikitin
Alexander Yu
AY
Weiss
Robert S
RS
D016475:3T3 Cells; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D000090063:Proto-Oncogene Mas; D012264:Ribonucleotide Reductases / Q000235:genetics*
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C102997:Msh6 protein, mouse; D000090063:Proto-Oncogene Mas; D012264:Ribonucleotide Reductases