The differential effects of mutant p53 alleles on advanced murine lung cancer.
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.
Jackson
Erica L
EL
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02141, USA.
Olive
Kenneth P
KP
Tuveson
David A
DA
Bronson
Roderick
R
Crowley
Denise
D
Brown
Michael
M
Jacks
Tyler
T
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000483:Alleles; D000818:Animals; D018450:Disease Progression; D016158:Genes, p53 / Q000235:genetics*; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010255:Paranasal Sinus Neoplasms / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation; D048490:raf Kinases / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D048490:raf Kinases