title: Isoform-Specific Effects of Wild-Type Ras Genes on Carcinogen-Induced Lung Tumorigenesis in Mice.
abstract: The gene KRAS is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS and NRAS, can still be activated in the presence of oncogenic KRAS. Moreover, loss of any one of these three genes has been shown to increase the sensitivity of mice to the carcinogen urethane, which induces Kras mutation-positive early lung lesions. To determine the contribution of progressively disrupting Hras and Nras genes on urethane lung tumorigenesis, mice with different combinations of wild-type and null alleles of Hras and Nras were exposed with urethane and tumor burden was assessed. As previously reported, loss of one allele of Hras increased the sensitivity of mice to this carcinogen, and this effect was further exacerbated by the loss of the second Hras allele. However, loss of one or both alleles of Nras failed to alter tumor burden, either in the absence or presence of Hras, after exposure to urethane. Additionally, no obvious difference between lung lesions in mice with wild-type versus null alleles was detected, suggesting that wild-type Ras proteins may exert a tumor suppressive effects at the time of initiation, although other interpretations are certainly possible. In summary, these data suggest that in some genetic backgrounds inactivation of different wild-type Ras genes can have different effects on urethane-induced lung tumorigenesis.
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Jamie D
authors.initials: JD
authors.lastname: Weyandt
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Carney
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Pavlisko
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: MengMeng
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.|Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Counter
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014520:Urethane / Q000633:toxicity*
chemical_list: D007527:Isoenzymes; D025521:Tumor Suppressor Proteins; D014520:Urethane; D016283:Proto-Oncogene Proteins p21(ras)