| First Author | Jackson EL | Year | 2005 |
| Journal | Cancer Res | Volume | 65 |
| Issue | 22 | Pages | 10280-8 |
| PubMed ID | 16288016 | Mgi Jnum | J:103407 |
| Mgi Id | MGI:3609440 | Doi | 10.1158/0008-5472.CAN-05-2193 |
| Citation | Jackson EL, et al. (2005) The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res 65(22):10280-8 |
| abstractText | We report a direct comparison of the differential effects of individual p53 mutations on lung tumor growth and progression, and the creation of a murine model of spontaneous advanced lung adenocarcinoma that closely recapitulates several aspects of advanced human pulmonary adenocarcinoma. We generated compound conditional knock-in mice with mutations in K-ras combined with one of three p53 alleles: a contact mutant, a structural mutant, or a null allele. p53 loss strongly promoted the progression of K-ras-induced lung adenocarcinomas, yielding a mouse model that is strikingly reminiscent of advanced human lung adenocarcinoma. The influence of p53 loss on malignant progression was observed as early as 6 weeks after tumor initiation. Furthermore, we found that the contact mutant p53R270H, but not the structural mutant p53R172H, acted in a partially dominant-negative fashion to promote K-ras-initiated lung adenocarcinomas. However, for both mutants, loss-of-heterozygosity occurred uniformly in advanced tumors, highlighting a residual tumor-suppressive function conferred by the remaining wild-type allele of p53. Finally, a subset of mice also developed sinonasal adenocarcinomas. In contrast to the lung tumors, expression of the point-mutant p53 alleles strongly promoted the development of sinonasal adenocarcinomas compared with simple loss-of-function, suggesting a tissue-specific gain-of-function. |
