Decrease in K-ras p21 and Increase in Raf1 and Activated Erk 1 and 2 in Murine Lung Tumors Initiated by N-Nitrosodimethylamine and Promoted by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Ramakrishna, Gayatri; Perella, Christine M.; Birely, Lisa; Diwan, Bhalchandra A.; Fornwald, Laura W.; Anderson, Lucy M.

doi:10.1006/taap.2001.9344

Cited by 30 publications

(13 citation statements)

References 48 publications

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“…Activation of MAPK pathways often correlates with advanced tumor progression in mouse lung (32)(33)(34); however, as the only carcinoma detected in the Wild-type group exhibited no detectable MAPK-activation, this general hypothesis cannot explain the observed increase in MAPKactivation in Cx32-KO lung tumors. Interestingly, additional total deletion of p27 resulted in the loss of MAPK-activated lung tumors in DKO mice ( p < 0.001 compared to Cx32-KO, carcinoma, perhaps via increased MAPK pathway activation influenced by p27.…”

Section: Radiation Studymentioning

confidence: 58%

“…As β-catenin mutations are often associated with mouse liver tumorigenesis, we sequenced β-catenin exons 2 and 3 from the same liver tumors detailed above (28). We found no base substitutions in the commonly mutated codons (32,33,37,41) or any insertions or deletions in this same area. This suggests an oncogenic mechanism independent from mutation in these tumors that results in increased β-catenin protein levels.…”

Section: Analysis Of Potential Oncogenic Alterations In Liver and Lunmentioning

confidence: 94%

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Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

King

Lampe

2005

Cell Communication & Adhesion

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Connexin32 knockout mice (Cx32-KO) exhibit increased chemical and radiation-induced liver and lung tumorigenesis. This increased tumor incidence is associated with altered tumor biology including enhanced tumor progression and an increased percent of MAPK-active tumors. Likewise, mice lacking the tumor suppressor/cell cycle regulator p27Kip1 exhibit increased tumorigenesis in a variety of tissues following chemical and radiation induction. Interestingly, in a double-deficient mouse model (DKO), additional loss of p27Kip1 in a Cx32-KO background results in attenuation of liver and lung tumorigenesis as well as MAPK activation profiles, suggesting pathway interaction. While these mouse strains exhibit altered liver and lung tumor susceptibility following both chemical (DEN) and radiation (X-ray) induction protocols, comparisons of the resulting tumor incidence, multiplicity, tumor progression, and MAPK activation in response to these two distinct carcinogens underscores the separate influence of each individual gene on both tumor formation and activation of specific oncogenic pathways. Furthermore, these studies demonstrate that different carcinogens interact disparately with Cx32/p27Kip1 genotypic backgrounds in situ resulting in varied tumorigenic response.

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Section: Radiation Studymentioning

confidence: 58%

Section: Analysis Of Potential Oncogenic Alterations In Liver and Lunmentioning

confidence: 94%

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

King

Lampe

2005

Cell Communication & Adhesion

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“…Normal mouse lung tissue was used in our study, thus K-ras would be expected to act as a tumor suppressor in this context [4][5][6]21]. However, published studies in colon and mammary gland show CS to be a tumor promoter [22,23].…”

Section: Discussionmentioning

confidence: 99%

Elevated K-ras activity with cholestyramine and lovastatin, but not konjac mannan or niacin in lung—–Importance of mouse strain

Calvert

Tepper

Kammouni

et al. 2006

Biochemical Pharmacology

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Our previous work established that hypocholesterolemic agents altered K-ras intracellular localization in lung. Here, we examined K-ras activity to define further its potential importance in lung carcinogenesis. K-ras activity in lungs from male A/J, Swiss and C57BL/6 mice was examined. For three weeks, mice consumed either 2 or 4% cholestyramine (CS), 1% niacin, 5% konjac mannan (KM), or were injected with lovastatin 25 mg/kg three or five times weekly (Lov-3X and Lov-5X). A pair-fed (PF) group was fed the same quantity of diet consumed by the Lov-5X mice to control for lower body weights in Lov-5X mice. After three weeks, serum cholesterol was assayed with a commercial kit. Activated K-ras protein from lung was affinity precipitated with a Raf-1 ras binding domain-glutathione-S-transferase fusion protein bound to glutathione-agarose beads, followed by Western blotting, K-ras antibody treatment, and chemiluminescent detection. Only KM reduced serum cholesterol (in 2 of 3 mouse strains). In C56BL/6 mice treated with Lov-3X, lung K-ras activity increased 1.8-fold versus control (p = 0.009). In normal lung with wild-type K-ras, this would be expected to be associated with maintenance of differentiation. In A/J mice fed 4% CS, K-ras activity increased 2.1-fold (p = 0.02), which might be responsible for the reported enhancement of carcinogenesis in carcinogen-treated rats fed CS. KM feeding and PF treatment had no significant effects on K-ras activity. These data are consistent with the concept that K-ras in lung has an oncogenic function when mutated, but may act as a tumor suppressor when wild-type.

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“…Because the link between increased TCR expression on thymocytes after TCDD exposure and increased ERK phosphorylation and Lck expression in HY-TCR Tg male mice was not formally tested in these studies, there are clearly alternative explanations for our data. Exposure to TCDD has been shown to alter mitogen-activated protein kinase signaling in a number of models (Lai et al, 1997;Jeon and Esser, 2000;Davis et al, 2001;Ramakrishna et al, 2002;Tsukumo et al, 2002;Kwon et al, 2003). For example, TCDD exposure resulted in increased ERK1/2 activation in murine lung tumors induced by N-nitrosodimethylamine, possibly as a result of increased raf-1 (Ramakrishna et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to TCDD has been shown to alter mitogen-activated protein kinase signaling in a number of models (Lai et al, 1997;Jeon and Esser, 2000;Davis et al, 2001;Ramakrishna et al, 2002;Tsukumo et al, 2002;Kwon et al, 2003). For example, TCDD exposure resulted in increased ERK1/2 activation in murine lung tumors induced by N-nitrosodimethylamine, possibly as a result of increased raf-1 (Ramakrishna et al, 2002). In addition, in vitro exposure of human Jurkat T cells to TCDD has been shown to result in ERK1/2 activation (Kwon et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin Enhances Negative Selection of T Cells in the Thymus but Allows Autoreactive T Cells to Escape Deletion and Migrate to the Periphery

Fisher¹,

Nagarkatti²,

Nagarkatti³

2004

Mol Pharmacol

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Exposure to 2,3,7,, an environmental pollutant, has been shown to cause thymic atrophy and apoptosis. However, whether TCDD alters the process of T-cell selection in the thymus is not clear. To this end, we investigated the effects of TCDD in the context of the HY-T-cell receptor (TCR) transgenic (Tg) mouse model. We noted that negatively selecting male HY-TCR Tg mice were significantly more sensitive to the thymotoxic effects of TCDD relative to positively selecting female HY-TCR Tg mice, including increased reduction in cellularity and increased induction of apoptosis. TCDD exposure also altered the thymocyte subset composition in HY-TCR Tg male but not female mice. In addition, TCDD treatment resulted in increased extracellularly regulated kinase phosphorylation and lymphocyte-specific protein tyrosine kinase expression in thymocytes of HY-TCR Tg male but not female mice. The increase in proportion of CD8 ϩ mature thymocytes noted in HY-TCR Tg male mice was reflected in the periphery, with TCDD-exposed HY-TCR Tg male mice having increased numbers of CD8 ϩ T cells. Finally, we noted that the proliferative response of HY-TCR Tg male T cells to HY(self)-Ag was enhanced after exposure to TCDD, whereas that of HY-TCR Tg female mice was decreased. Taken together, these data suggest that TCDD alters the process of thymic selection, possibly by enhancing negative thymocyte selection, whereas at the same time allowing autoreactive T cells to escape deletion in the thymus and immigrate to the periphery.

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Decrease in K-ras p21 and Increase in Raf1 and Activated Erk 1 and 2 in Murine Lung Tumors Initiated by N-Nitrosodimethylamine and Promoted by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Cited by 30 publications

References 48 publications

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

Elevated K-ras activity with cholestyramine and lovastatin, but not konjac mannan or niacin in lung—–Importance of mouse strain

2,3,7,8-Tetrachlorodibenzo-p-dioxin Enhances Negative Selection of T Cells in the Thymus but Allows Autoreactive T Cells to Escape Deletion and Migrate to the Periphery

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Decrease in K-ras p21 and Increase in Raf1 and Activated Erk 1 and 2 in Murine Lung Tumors Initiated by N-Nitrosodimethylamine and Promoted by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Cited by 30 publications

References 48 publications

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27Kip1-Deficient Mice

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27Kip1-Deficient Mice

Elevated K-ras activity with cholestyramine and lovastatin, but not konjac mannan or niacin in lung—–Importance of mouse strain

2,3,7,8-Tetrachlorodibenzo-p-dioxin Enhances Negative Selection of T Cells in the Thymus but Allows Autoreactive T Cells to Escape Deletion and Migrate to the Periphery

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Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27^Kip1-Deficient Mice