The retinoblastoma gene Rb and its family member p130 suppress lung adenocarcinoma induced by oncogenic K-Ras.
Mutations of the retinoblastoma tumor suppressor gene RB are frequently observed in human cancers, but rarely in non-small cell lung carcinomas (NSCLCs). Emerging evidence also suggests that the RB-related gene p130 is inactivated in a subset of human NSCLCs. To directly test the specific tumor suppressor roles of RB and p130 in NSCLC, we crossed Rb and p130 conditional mutant mice to mice carrying a conditional oncogenic K-Ras allele. In this model, controlled oncogenic K-Ras activation leads to the development of adenocarcinoma, a major subtype of NSCLC. We found that loss of p130 accelerated the death of mice, providing direct evidence in vivo that p130 is a tumor suppressor gene, albeit a weak one in this context. Loss of Rb increased the efficiency of lung cancer initiation and resulted in the development of high-grade adenocarcinomas and rapid death. Thus, despite the low frequency of RB mutations in human NSCLCs and reports that K-Ras activation and loss of RB function are rarely found in the same human tumors, loss of Rb clearly cooperates with activation of oncogenic K-Ras in lung adenocarcinoma development in mice.
Ho
V M
VM
Department of Pediatrics and Genetics, Stanford Medical School, Stanford, CA 94305-5149, USA.
Schaffer
B E
BE
Karnezis
A N
AN
Park
K S
KS
Sage
J
J
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016161:Genes, Retinoblastoma / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000502:physiology*
C493838:Rbl2 protein, mouse; D050717:Retinoblastoma-Like Protein p130; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)