PA Author Manuscript Figure 1 Development of skin tumors in M Mice ATM and p53-deficient LDN193189 A, DMBA / TPA-induced papillomas in mice deficient ATM-M. The average number of papillomas per mouse of the indicated size E class plotted against time after DMBA treatment. B is the average number of papillomas in all sizes Mouse Atm genotype enklassen shown time after DMBA treatment applied. C, surviving cancer in DMBA / TPA-treated Mice. . D, tumor-free survival in DMBA / TPA-treated Mice. . E, DMBA / TPA-induced papillomas and Trp53F2-10/F2-10 Trp53F2-10/F2-10, K14-Cre mice M. The number of papillomas in p53-deficient M Mice at 23 and 25 weeks was larger It as a wild species. F, cancer-free survival DMBA / TPA treated wt p53 and p53-specific skin removed. The difference was highly significant.
Bailey et al. Page 11 Mol Cancer Res author manuscript in PMC 2009 1 July. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Figure 2 Signaling pathways in DNA Sch In the Atm-deficient papillomas A, H & E found Rbten sections and immunostaining Staining for the indicated proteins In papillomas of wild-type, Atm And ARF Mice. Top row was photographed Nutlin-3 with a mag TION of last 100x and 600x lower in line. B, quantification of-H2AX γ, pChk2, the index of p53, apoptosis and mitosis in Atm + / +, Atm And ARF Papillomas. The values were calculated in color than the average difference over the standard number of cells found for H2AX-γ, pChk2, p53, or apoptosis, or mitotic figures per 400x field. P-values were determined using the Mann-Whitney. Bailey et al.
Page 12 Mol Cancer Res author manuscript in PMC 2009 1 July. NIH-PA Author Manuscript NIH-PA-PA Author Manuscript Author Manuscript NIH third figure The loss of p53 and Atm cooperate in tumorigenesis A spontaneous tumor development in ATM accelerated �p 53 Atm mouse over or p53 Mouse. B, IR-induced tumor development in all genotypes except Atm accelerated Mice. atm �p 53 Mice develop tumors faster than ATM or p53 Mouse. C, IR-induced apoptosis in the thymus of mice 3 weeks old M. The values are the mean and standard deviation of apoptotic figures per 400x field for 3 � M mice Per genotype. Bailey et al. Page 13 Mol Cancer Res author manuscript in PMC 2009 1 July.
Author Manuscript NIH-PA Author Manuscript NIH-PA-PA Author Manuscript NIH Figure 4 P53 LOH was seen in the tumors of two ATM + / + and Atm Mouse PCR analysis shows loss of the wild-type allele of p53 in 4/7 spontaneous and 8/9 IR-induced tumors of ATM �p 53 + / Mice and tumors from 7:04 p53 + / Mouse. * Indicates LOH of p53 in tumors. Weight = wild-type p53 allele, mu = mutated p53 allele. Bailey et al. Page 14 Mol Cancer Res author manuscript in PMC 2009 1 July. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript-PA Author Manuscript NIH-PA Author Manuscript NIH Bailey et al. Page 15 mice Frequency conversion of papillomas to carcinomas Table 1 for M At least 20 weeks after DMBA Mice genotype Number Total Total # of papillomas and carcinomas lived frequency conversion of p-value vs. ATM + / + ATM 7121 6 5.0% + 1 ATM / 33 664 55 0.11 8.
3% ATM + / + 25 503 28 5.6% N / A Mol Cancer Res author manuscript in PMC 2009 1 July. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Bailey et al. Page 16 Table 2 Spectrum of tumors in M Mice ATM and p53-deficient irradiated spontaneous P53 AT P53 + / AT P53 + / + A + / + p53 AT p53 AT p53 + / AT p53 + / + A + / + p53 �T hymoma / lymphoma 9 9 12 9 4 11 4 8 sarcoma 1 0 0 2 0 0 0 1 testicular tumor 0 0 0 2 0 0 0 2 Brain Tumor 0 0 0 1 0 0 0 Several 0 2 1 0 2 0 0 0 Other 0 1 1 2 1 0 0 1 0 Total 13 11 14 17 4 11 5 11