Ki‐ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice

Mass, Marc J.; Ross, Jeffrey A.; Nesnow, Stephen; Jeffers, A. J.; Nelson, Garret B.; Galati, Anthony J.; Stoner, Gary D.

doi:10.1002/mc.2940080309

Cited by 67 publications

(46 citation statements)

References 19 publications

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“…These results are in accordance with previous studies (Kobayashi et al, 1990;Westra et al, 1993;Rodenhuis et al, 1997). Benzo(a)pyrene, and nitrosamines, considered to be the major carcinogenic compounds of tobacco smoke (Loeb et al, 1984;Carothers, 1990), have been demonstrated to induce mostly G to T transversion in experimental murine models of lung tumours harbouring a K-ras mutation restricted to codon 12 (You et al, 1989(You et al, , 1993Mass et al, 1993).…”

Section: Detection Of K-ras Mutations In Bronchial Carina 415supporting

confidence: 92%

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

Urban

Ricci²,

Danel

et al. 2000

Br J Cancer

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K- ras activation by point mutation in codon 12 has been reported in lung adenocarcinomas in various models of experimental lung tumours induced by chemical carcinogens. The hypothesis of the presence of cells containing K- ras mutation in non neoplastic bronchial carina, the main site of impaction of airborne contaminants, was investigated by evaluating concurrent lung tumour and non-neoplastic proximal bronchial carinae from 19 patients with lung adenocarcinomas. The restriction fragment length polymorphism enriched PCR method used can detect one mutant allele among 10 3 normal alleles. A mutation was detected in 42% of lung adenocarcinoma samples. No mutation was detected in either tumour or bronchial carinae in nine patients (47%). K- ras mutation was detected in the lung tumour but not in bronchial carinae in four patients (21%), in both the lung tumour and bronchial carinae in four other patients (21%). In two patients (11%), K- ras mutation was detected in at least one bronchial carina, but not in the lung tumour. Mutations of codon 12, confirmed by sequencing analysis of ten samples, were G to T transversion, mostly TGT and GTT in bronchial carinae and lung tumours. Our data show that activated K- ras by point mutation can be present in non-neoplastic bronchial carina mucosa even when no mutation is detected in tumour samples. © 2000 Cancer Research Campaign

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Section: Detection Of K-ras Mutations In Bronchial Carina 415supporting

confidence: 92%

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

Urban

Ricci²,

Danel

et al. 2000

Br J Cancer

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“…Furthermore, it has been shown that the K-ras codon 12 mutation is the most frequent mutation observed in benzopyrene-induced carcinomas (39). Therefore, it is likely that the majority of benzopyrene-treated mice in our study had codon 12 mutations in the K-ras gene.…”

Section: Discussionmentioning

confidence: 74%

Human Cancer-Associated Mutations in the Aα Subunit of Protein Phosphatase 2A Increase Lung Cancer Incidence in Aα Knock-In and Knockout Mice

Ruediger

Ruiz

Walter

2011

Molecular and Cellular Biology

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Strong evidence has indicated that protein phosphatase 2A (PP2A) is a tumor suppressor, but a mouse model for testing the tumor suppressor activity was missing. The most abundant forms of trimeric PP2A holoenzyme consist of the scaffolding A␣ subunit, one of several regulatory B subunits, and the catalytic C␣ subunit. A␣ mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant A␣ subunits are defective in binding the B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated A␣ point mutants defective in binding B subunits, one knockout mouse expressing truncated A␣ defective in B and C subunit binding, and a floxed mouse for generating conditional A␣ knockouts. We found that the cancer-associated A␣ mutations increased the incidence of cancer by 50 to 60% in lungs of FVB mice treated with benzopyrene, demonstrating that PP2A acts as a tumor suppressor. We show that the effect of A␣ mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that the A␣ mutation E64D, which was detected in a human lung carcinoma, increases the lung cancer incidence in mice suggests that this mutation also played a role in the development of the carcinoma in which it was discovered.Protein phosphatase 2A (PP2A) plays a role in many fundamental cellular processes, such as signal transduction, DNA repair, transcription, translation, and growth control (15,24,26,43,77). The basis for this multifunctionality of PP2A rests on the large number of subunits that control its phosphatase activity, substrate specificity, and subcellular localization. The trimeric holoenzyme is composed of a catalytic C subunit, a scaffolding A subunit, and one of many regulatory B subunits. The dimeric core enzyme consists of one A and one C subunit. Both forms coexist in cultured cells and in tissue (5,30,42). The A subunit exists as two isoforms, A␣ and A␤, which are 87% identical. The catalytic C subunit also exists as two isoforms, C␣ and C␤, which are 96% identical. The B subunits fall into four families designated B, BЈ, BЉ, and Bٞ. The B or PR55 family has four members, the BЈ family (also designated B56 or PR61) consists of five isoforms and additional splice variants, and the BЉ or PR72 family has four members, including splice variants. B, BЈ, and BЉ are largely unrelated by sequence except for two common regions involved in binding to the A subunit (34). The Bٞ family has two members, striatin and S/G 2 nuclear autoantigen (40). The combination of all subunits could give rise to over 70 different holoenzymes. In addition, the ability of PP2A to associate with approximately 150 other proteins further increases its regulatory potential (15,24,26,42). Figure 1 shows a schematic diagram of the BЈ-containing holoenzyme whose structure has been revealed by biochemical analysis (53, 56) and X-ray crystallography (9,19,44,78,79).The first indication that PP2A might be a tumor suppressor came from the finding that okadaic acid is both a tumor promoter and an inhibitor of...

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“…For example, in the strain A mouse highly susceptible to spontaneous and inducible lung tumours, Ki-ras point mutations in spontaneous lung tumours were found in both codons 12 (60%) and 61 (30%) (You et al, 1989(You et al, , 1993Mass et al, 1993). After tumour induction in this mouse strain, the pattern of Ki-ras mutation was different according to the carcinogen used: in codon 12 for 100% of tumours after induction by methyl nitrosourea and 93% after benzo[a]pyrene exposure, in contrast, 90% of the mutations after ethyl carbonate exposure were situated in codon 61 (You et al, 1989).…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, in another series from Spain, Ki-ras mutations were not only detected in adenocarcinomas, but the majority of Kiras mutations were present in squamous cell carcinomas (Rosell et al, 1993). In experimental models of lung tumours conducted in different mouse strains, various chemical carcinogens have been demonstrated to induce tumours harbouring a Ki-ras mutation restricted to codon 12 [You et al, 1989[You et al, , 1993Mass et al, 1993). These human and experimental data suggest that codon 12 of Ki-ras may be a specific target for the mutagenic activity of various compounds of tobacco smoke (HusafvelPursiaisen et al, 1993).…”

mentioning

confidence: 99%

Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung

Urban

Ricci²,

Lacave³

et al. 1996

Br J Cancer

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Summary Ki-ras activation by point mutation on codon 12 has been reported in non-small-cell lung carcinomas and in various models of experimental lung tumours induced by chemical carcinogens. The cellular targets for carcinogenic compounds of tobacco smoke are usually considered to be the cells of the bronchial mucosa or alveolar epithelium. However, little is known about preneoplastic events in bronchopulmonary carcinogenesis. The hypothesis of the presence of widespread target cells containing Ki-ras mutation was investigated by evaluating concurrent neoplastic and non-neoplastic bronchial and alveolar samples from 51 patients with non-small-cell lung carcinomas. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method used can detect one cell with a mutation on codon 12 among 102 normal cells. In tumour samples, a mutation was detected in 20% of adenocarcinomas, but in none of the adenosquamous or squamous cell carcinomas. No mutation was detected in the non-neoplastic bronchial or parenchymal samples. When using an enriched PCR-RFLP method detecting one mutated allele among 103 normal alleles a mutation was detected in 23% of adenocarcinomas. In conclusion, Ki-ras activation by mutation on codon 12 was not observed in non-neoplastic bronchial or parenchymal tissues in patients with bronchopulmonary cancers and does not appear to be a genetic event present in non-malignant epithelial target cells exposed to tobacco smoke.

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Ki‐ras oncogene mutations in tumors and DNA adducts formed by benz[j]aceanthrylene and benzo[a]pyrene in the lungs of strain A/J mice

Cited by 67 publications

References 19 publications

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

Human Cancer-Associated Mutations in the Aα Subunit of Protein Phosphatase 2A Increase Lung Cancer Incidence in Aα Knock-In and Knockout Mice

Codon 12 Ki-ras mutation in non-small-cell lung cancer: comparative evaluation in tumoural and non-tumoural lung

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