Lung-Specific Expression of Dominant-Negative Mutant p53 in Transgenic Mice Increases Spontaneous and Benzo(a)pyrene-Induced Lung Cancer

Tchou-Wong, Kam Meng; Jiang, Yixing; Yee, Herman; LaRosa, Jennifer; Lee, Theodore C.; Pellicer, A.; Jagirdar, Jaishree; Gordon, Terry; Goldberg, Judith D.; Rom, William N.

doi:10.1165/ajrcmb.27.2.4799

Cited by 24 publications

(16 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PP2A mutant mice were backcrossed to strain FVB, because FVB mice have a predisposition for lung cancer (20% incidence at 18 months of age) (36,71). When used for the cancer studies, they were at the N7 generation (99.2% FVB).…”

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

“…When used for the cancer studies, they were at the N7 generation (99.2% FVB). Transgenic FVB mice expressing a dominant negative mutant of p53 (dnp53) under the control of the lung-specific promoter for the Clara cell-specific protein (CCSP) were generously provided by Kam Meng Tchou-Wong (71). One E64D/ϩ; dnp53 male was mated 2 to 3 times FIG.…”

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

“…The sequence of E64D mRNA from liver and kidney of E64D mice was also correct. (71,75). One g of BP was dissolved (suspended) in 50 ml tricaprylin (catalog number T9216; Sigma) to 0.02 mg/l at 37°C with gentle shaking over several hours and then spun once at 2,000 ϫ g for 3 min.…”

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

“…In contrast, loss of p53 tumor suppressor activity is rare in genetically or chemically induced murine lung carcinomas (37). Nevertheless, mice have been a useful model for investigating the role of p53 in lung carcinogenesis (71,75,76,82). We asked whether loss of PP2A tumor suppressor activity enhances the oncogenic effect of p53 inactivation.…”

mentioning

confidence: 99%

“…We asked whether loss of PP2A tumor suppressor activity enhances the oncogenic effect of p53 inactivation. To answer this question, we used the system developed by Tchou-Wong et al (71), who demonstrated that elimination of p53 tumor suppressor activity by expression of the dominant negative p53 mutant, dnp53 (61), doubles the lung cancer incidence in FVB FIG. 11.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

Section: Fig 2 Generation Of E64d Mice (A)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

Lung Cancer

Kurie

Minoo

Hecht

et al. 2004

Mouse Models of Human Cancer

View full text Add to dashboard Cite

Lung cancer most often stems from a single environmental cause but has diverse genetic, biochemical, and histologic characteristics. This diversity has made the basic causes of lung cancer difficult to surmise. Current mouse models support genetic alterations in lung epithelial cell transformation, but these models do not recapitulate the diversity of histologic appearance, site of origin, or natural history of lung cancer in humans. Advances in mouse model technology provide hope that the significance of the myriad genetic and biochemical alterations in human lung cancer will eventually be understood and that future models will better represent their human counterpart. Progress in this area will enhance both the basic understanding of lung tumorigenesis and the speed with which the anticancer efficacy of investigational drugs can be investigated in preclinical trials.

show abstract

In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung ofgpt delta transgenic mice

Hashimoto

Amanuma

Hiyoshi

et al. 2005

Environ. Mol. Mutagen.

View full text Add to dashboard Cite

Benzo[a]pyrene (B[a]P) is a ubiquitous airborne pollutant whose mutagenicity has been evaluated previously by oral and intraperitoneal administration to experimental animals. In this study, mutagenesis in the lungs, the target organ of air pollutants, was examined after a single intratracheal instillation of 0-2 mg B[a]P into gpt delta transgenic mice. Intratracheal injection of B[a]P resulted in a statistically significant and dose-dependent increase in gpt mutant frequency as measured by 6-thioguanine selection. The mutant frequencies at B[a]P doses of 0.5, 1, and 2 mg were 2.8, 4.2, and 6.8 times higher than the frequency seen in nontreated mice (0.60 +/- 0.13 x 10(-5)). The most frequent mutations induced by B[a]P treatment were G:C-->T:A transversions, which are characteristic of B[a]P mutagenesis in other models, and single-base deletions of G:C base pairs. To characterize the hotspots of B[a]P-induced mutations in the gpt gene, we analyzed sequences adjacent to the mutated G:C base pairs. Guanine bases centered in the nucleotide sequences CGT, CGA, and CGG were the most frequent targets of B[a]P. Our results indicate that intratracheal instillation of B[a]P into gpt delta mice causes a dose-dependent increase in gpt mutant frequency in the lung, and that the predominant mutation induced is G:C-->T:A transversion.

show abstract

Lung-Specific Expression of Dominant-Negative Mutant p53 in Transgenic Mice Increases Spontaneous and Benzo(a)pyrene-Induced Lung Cancer

Cited by 24 publications

References 24 publications

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

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

Lung Cancer

In vivo mutagenesis induced by benzo[a]pyrene instilled into the lung ofgpt delta transgenic mice

Contact Info

Product

Resources

About