Is a tumor suppressor p53, which induces the activation in response to oncogenic 36, 41 We have previously shown accelerated papilloma progression of cancers deficient M Mice using an identical Arf DMBA / TPA protocol 24th Compared with wild-type papillomas and ATM-null Mice showed reduced expression of Arf 0 papillomas of p53 and H2AX F Staining KW 2449 and increased Hte mitotic activity t. This is best Confirms our previous findings that ARF plays a role Essential in the induction of p53 in benign tumor growth. Reduced p53 explained Ren k nnte The increased Hte proliferation of these tumors, which may contribute to increased Hten values of H2AX k. However, the p53 DNA-Sch Even in these tumors, the tumor-bearing irradiated Arf functional Mice showed robust induction of p53 in 24 papillomas.
These results, together with low pChk2 in untreated papillomas shows that the level of DNA-Sch Ending may be sufficient in untreated tumors, a response to DNA damage triggered St. And tumor suppression by p53, at least in this model of epithelial VX-680 cancer, is governed by the selection against Arf and p53 is entered Arf by oncogenic signaling by birth. Compared with epidermal cells, ATM has an R Most important in the regulation of p53 in lymphoid cells Of 17, so we also examined the interaction of p53 and ATM induced in spontaneous and IR models lymphomas. The latency for the development of spontaneous tumors in atm Mice were shorter than the p53 Mice.
The latency of the tumors was significantly accelerated in atm P53 Made mouse Mutants compared to either single mutant alone, consistent with a previous study 49th ~ 95% of the ATM And atm P53 M Presented use CD3 positive T cells developed lymphoma, the thymidine as extended, with the occasional spleen or lymph nodes. The spectrum of tumors is slightly different in the p53 nulls. Thymic lymphoma 60% and 40% other types of tumors, primarily developed sarcomas. Thus, the reduced tumor latency in atm P53 Mice is Haupts Chlich on the acceleration of thymic T-cell lymphomas. The expression of p53 by IR-induced apoptosis and is strong in lympho VER Changed Thymus of adult Atm 0 M Nozzles 51, which indicates that the ATM plays a role In the central control of p53 and apoptosis in these cells. We initially Highest to check whether the IR-induced apoptosis in thymocytes from young Atm-deficient M Mice adversely Chtigt was.
The results in Figure 3C show pr presents Reduced apoptosis in irradiated Atm Thymus of the wild-type siblings compared. If the ATM-dependent Ngigen apoptotic signaling pathway is crucial for the suppression of tumors, is a prediction that the seed should Atm deficiency effectively to neutralize p53 in a model of radiation-induced tumor. Another group of mice M Was two days old with a single dose of 1.4 Gy radiation reduced the latency to the neonatal treated tumor development in p53 Mice From a median of 141 days to 100 days. However, no significant influence on radiation tumor development in atm Mice. The median age at tumor development in irradiated Atm Mice was 113 days compared to 116 days in the unexposed cohort.
latency tumors in irradiated Atm �p 53 Mutants compounds were also reduced compared to either single mutant alone. The predominant type of tumor in all irradiated genotypes was CD3 positive T-cell lymphomas, with an incidence of 95%. Bailey et al. Page 4 Mol Cancer Res author manuscript in PMC 2009 1 July. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript We then asked whether the loss of ATM or reduced selection against p53 eliminates need during the tumor development, by examining loss of heterozygosity of p53 in tumors ATM P53 + / Mouse. 50% of spontaneous thymic lymphomas and 89% of IR-induced lymphomas in ATM �p 53 + / Mice showed a loss of p53 wild-type allele. This is comparable to the loss of 57% of lymphomas in p53 + p53 / Micro