Browsing by Subject "Carcinogenesis"
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Item A mutagenesis assay for the carcinogen 1,2-dimethylhydrazine(Texas Tech University, 1979-08) Wells, Barbara C.Not availableItem ATM promotes apoptosis and suppresses tumorigenesis in response to Myc(2008-12) Pusapati, Raju V. L. N., 1969-; Johnson, David, 1963-; Richburg, John H.Precancerous lesions from a variety of human tissues display markers of DNA damage suggesting that genetic instability occurs early during the process of carcinogenesis. Consistent with this, several oncogenes can activate ATM and other components of the DNA damage response pathway when expressed in cultured cells. Here we demonstrate that preneoplastic epithelial tissues from four different transgenic mouse models expressing the oncogenes c-myc, SV40 T antigen, human papilloma virus (HPV) E7, or E2F3a display [gamma]-H2AX foci and other markers of DNA damage. Moreover, transgenic expression of these oncogenes leads to increased levels of damaged DNA as measured by the comet assay. In at least the Myc transgenic model, the formation of [gamma]-H2AX foci is dependent on functional ATM. Inactivation of Atm also impairs p53 activation and reduces the level of apoptosis observed in transgenic tissue overexpressing Myc. This correlates with accelerated tumor development in Myc transgenic mice lacking ATM. To understand the mechanism by which oncogenes induce DNA damage, we employed an adenoviral overexpression system. Under conditions in which Myc or E2F3a induced replication is inhibited, we see a reduction in the DNA damage induced by these oncogenes both by comet assay and levels of [gamma]-H2AX. Moreover, Myc and E2F3a induced increased levels of the Cdt1 protein, a replication origin- licensing factor implicated in aberrant DNA replication. Taken together, these findings suggest that deregulated oncogenes induce unscheduled DNA replication leading to DNA damage and activation of the ATM DNA damage response pathway, which is important for the activation of p53, induction of apoptosis and the suppression of tumorigenesis.Item DNA-damaging effects of 1,2-dimethylhydrazine on Bacillus subtilis(Texas Tech University, 1978-08) Hoffman, Kent M.The DNA-damaging potential of the compound 1,2-diinethylhydrazine (DMH) was investigated using the Bacillus subtilis tester systems, which included the DNA repair assay, DNA-DMH binding studies, and DNA transformation. The compound was shown to specifically inhibit the growth of recombination deficient strains of B^. subtilis more than the wild type strain. For DNA-damaging activity, the pH had to be above 6.5. Below this pH, the compound did not appear to be active. Activation with rat-liver homogenate did not increase the DNA-damaging activity. The absorption spectrum of DNA isolated from the recombination deficient strain, mc-1, was altered when the DNA was challenged 2J1 vivo with DMH but not when challenged iji vitro. Transformation with treated DNA from this strain was reduced compared to DNA isolated from an unchallenged culture.Item E2F3a functions as an oncogene and induces DNA damage response pathway mediated apoptosis(2007) Paulson, Qiwei Xia, 1974-; Johnson, David, 1963-; Bratton, Shawn B.Mutation or inactivation of RB occurs in most human tumors and results in the deregulation of several E2F family transcription factors. Among the E2F family, E2F3 has been implicated as a key regulator of cell proliferation and E2f3 gene amplification and overexpression is detected in some human tumors. To study the role of E2F3a in tumor development, we established a transgenic mouse model expressing E2F3a in a number of epithelial tissues via a keratin 5 (K5) promoter. Transgenic expression of E2F3a leads to hyperproliferation, hyperplasia and increased levels of p53-independent apoptosis in transgenic epidermis. Consistent with data from human cancers, the E2f3a transgene is found to have a weak oncogenic activity on its own and to enhance the response to a skin carcinogenesis protocol. While E2F3a induces apoptosis in the absence of p53, the inactivation of both p53 and p73, but not p73 alone, significantly impairs apoptosis induced by E2F3a. This suggests that both p53 and p73 contribute to E2F3a induced apoptosis but that their function is compensatory. Even though data suggest that E2F3a carries out its unique apoptotic activity in part through another E2F family member E2F1, unlike E2F1, the ARF tumor suppressor is required for E2F3a-induced apoptosis. While both E2F3a and E2F1 require ATM for apoptosis, E2F3a activates ATM through a distinct mechanism from E2F1. The overexpression of E2F3a results in the accumulation of DNA damage in K5 transgenic keratinocytes and normal human fibroblasts (NHFs). In response to this, the DNA damage checkpoint kinase ATM is activated, and phosphorylation of the downstream targets p53 and the histone variant H2AX are significantly increased. Additional studies show that increased Cdk activity and aberrant DNA replication contributes to DNA damage, ATM activation and apoptosis in response to deregulated E2F3a, which suggest that aberrant replication imposed by deregulated E2F3a plays an important role in the activation of the ATM DNA damage response pathway. Activation of ATM by E2F3a is not affected by loss of ARF or E2F1. Meanwhile, E2F3a-induced ARF upregulation is not affected by E2F1 loss. The above results indicate that E2F3a engages several parallel pathways involving E2F1, ARF and the ATM kinase, and these pathways cooperate to promote apoptosis.Item Effect of dietary selenium and fat on the incidence of spontaneous mammary tumorigenesis of Cb3sH/StHa mice(Texas Tech University, 1985-12) Stoltenberg, PeggyThe purpose of this present study was to combine two dietary variables (Se 0, 0.1, 1.0 ppm and polyunsaturated fat as safflower oil or saturated fat as coconut oil) and observed the incidence and development of spontaneous mammary tumors in C-.H/StHa mice.Item Effect of graded levels of molybdenum supplementation on n-methyl-n-nitrosourea-induced mammary carcinogenesis in female rats(Texas Tech University, 1984-08) Seaborn, Carol DeanNot availableItem Effect of tallow and corn oil on the metabolism of 2-acetylaminofluorene (ACAF) in rats(Texas Tech University, 1977-08) Castro, Carmen ElizabethNot availableItem Quantitation of a mutagenic metabolite produced from 1,2-dimethylhydrazine during lipid influenced colon cancer development by a Bacillus subtilis assay(Texas Tech University, 1981-05) Wargovich, Michael JohnStudies were conducted to determine if the impact of the growth management plan adopted by Petaluma, California in 1972 for a five-year period, accomplished the goals and objectives established at the onset of the program. Uniform data were gathered for Petaluma and four control cities of similar size and location. The data were tested using Friedman's two-way analysis of variance by ranks test to determine likeness between the cities. Thirteen variables were selected to obtain an overview of characteristics relating to general information, revenue data, expenditure data, and debt information. The results of these tests indicated the five communities appeared strikingly similar in the period 1940-1970. Since Petaluma adopted its growth management scheme in 1972, the cities tested appear significantly different. To determine if that difference could be explained due to the growth management policies of Petaluma, five specific goals for the plan which were given by the city as reasons for taking the new planning approach were stated as hypotheses and tested. It was originally stated that adoption of a growth management planning scheme would lower the tax burden on the local taxpayer. The results of the tests do not support this statement; in fact, it appears the plan increased the local tax burden and reduced the citizens cost : benefit ratio with respect to the public services and facilities. Protecting and enhancing the environmental quality of new single and multifamily development projects was a cornerstone of the rationale for adoption of the growth management approach. The results of the test indicate projects in the control cities were of comparable environmental quality to those in Petaluma. The third goal set by Petaluma as the city embarked on its growth management program was the provision of 8 to 12 percent annually of new housing stock at a cost which was affordable to the city's low and moderate income citizens. The results of the study indicate the Residential Development Control System, which is used to implement the city's new planning scheme is ineffective in achieving this goal. The point allocation system rewards additional amenities with higher points and actually works against developments designed for low and moderate income families. Petaluma's plan requires all development proposals to be reviewed at the same time, so the volume of business in the planning department becomes feverish as the time for review and evaluation approaches. Has the impact of the new review schedule caused the city of Petaluma to increase the size of its planning staff? The test results indicate each city had different size planning staffs in relation to their population size and they continue to be as they were. It was found that adopting growth management planning, per se, could not be directly associated with the political fortunes of the city's elected officals. However, when the issue remained local, the effect divided voters into camps for and against the issue. When the city attracted national attention, the local voters rallied behind their officials and their plan. The final goal set by the city was to balance new growth in the city so all three sectors shared in the development of the city. Analysis of the study data reveals that this goal was achieved extremely well. Goals set for each of the three sectors were within two percentage points of being right on target. In summary, it appears that growth management planning policies are effective in achieving allocation goals, but are not as capable of achieving economic goals.Item The role of EP1 receptor for prostaglandin E₂ in mouse skin carcinogenesis(2009-05) Surh, In Ok; Fischer, Susan M.; Bratton, Shawn B.Prostaglandin E₂ (PGE₂), the most abundant prostaglandin in mouse skin, has been shown to promote skin tumor development. EP1 is one of four PGE₂ receptors. EP1 mRNA levels analyzed by a quantitative real-time polymerase chain reaction were increased after treatments of 12-O-tetradecanoylphorbol 13-acetate (TPA) or ultraviolet light on skin as well as in 7,12 dimethylbenz[a]anthracene (DMBA)/TPA or UV-induced skin tumors. To determine whether the EP1 receptor levels affect skin tumor development, we generated BK5.EP1 transgenic mice which overexpress EP1 in the basal layer of the epidermis. The skins of these mice are histologically indistinguishable from wild type mice. To determine the role of EP1 in skin tumor development, a DMBA/TPA skin carcinogenesis protocol was used. EP1 transgenic mice had a reduced tumor multiplicity and a reduced tumor incidence compared to wild type mice, but had a higher papilloma to carcinoma conversion rate. In a DMBA-only skin carcinogenesis protocol, EP1 transgenic mice developed more tumors than wild type mice. The effect of EP1 on cell proliferation was measured in vivo. After TPA treatment, cell proliferation was induced in both EP1 transgenic mice and wild type mice to a similar extent. However, 5 days after DMBA treatment, there were about 2-fold more proliferating cells in the basal layer of the epidermis of EP1 transgenic mouse skin than in wild type mice. To confirm that the enhanced tumor formation in transgenic mice is in fact PGE₂ dependent, EP1 transgenic mice were administered the selective cyclooxygenase-2 inhibitor Celecoxib or a control diet starting 1 week before DMBA treatment. Surprisingly, there was no lesion development on mice that were fed Celecoxib. Histological sections of skin from Celecoxib-fed mice showed a fairly normal skin histology 2 weeks after DMBA treatment compared to the pronounced pseudocarcinomatous hyperplasia observed in control diet mice. Therefore, it can be concluded that EP1 signaling increases PGE₂ production through COX-2 induction and promotes tumor development.Item The role of the EP2 receptor for prostaglandin E2 in mouse skin carcinogenesis(2005) Sung, You Me; Fischer, Susan M.; Kline, KimberlyItem Transcriptional regulation and the role of murine 8S-lipoxygenase in mouse skin carcinogenesis(2004) Kim, Eunjung; Fischer, Susan M.8S-lipoxygenase (8S-LOX), the murine homolog of human 15S-LOX-2, has unique expression features in mouse skin, i.e., it is not expressed at a detectable level in normal skin but is strongly expressed in several stages of skin tumorigenesis, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) treated skin or in skin tumors. In this study, we studied a specific mechanism by which 8SLOX gene expression is regulated by TPA in keratinocytes and the functional role of 8S-LOX during mouse skin carcinogenesis. In the first study, we found TPAinduced 8S-LOX mRNA expression in SSIN primary mouse keratinocytes was the result of increased transcription. Therefore, transcriptional regulation of 8SLOX expression was further studied by cloning its promoter. The cloned 8S-LOX promoter (~ 2 kb) has neither a TATA box nor a CCAAT box, however, it was highly responsive to TPA in SSIN primary keratinocytes. We then identified a Sp1 binding site (-68/-77) as a TPA responsive element (TRE) in the promoter and showed that Sp1, Sp2, and Sp3 proteins bind to the TRE. Binding of these proteins to the TRE was significantly increased by TPA treatment and 8S-LOX transcription was decreased when the binding of these proteins was inhibited. We thus concluded that increased binding of Sp1, Sp2, and Sp3 to the TRE of the 8SLOX promoter is a mechanism by which TPA induces 8S-LOX expression in keratinocytes. In the second study, we found 8S-LOX is closely associated with keratinocyte differentiation and forced expression can inhibit mouse skin tumorigenesis. Targeted C57BL/6J transgenic mice overexpressing the 8S-LOX gene under control of the loricrin promoter exhibited more differentiated epidermal phenotypes as well as reduced papilloma development in a two-stage skin carcinogenesis protocol. Forced expression of the 8S-LOX gene in tumorderived cell lines, MT1/2 (papilloma) and CH72 (carcinoma), also caused increased differentiation and inhibition of cell proliferation in vitro as well as in in vivo xenografts, respectively. Moreover, histochemical analyses showed 8S-LOX expression was strictly confined to the differentiated region of the skin in the course of skin tumorigenesis. Collectively, these findings suggest that 8S-LOX plays a role as a prodifferentiating, an anticarcinogenic, and a tumor suppressing gene in mouse skin.