Abstract
AbstractMice engineered with G12D versus Q61R mutant of Kras exhibit differences in the number and grade of tumors. Namely, the incidence or grade of oral or forestomach squamous epithelial lesions was more prevalent in the KrasG12Dbackground while hematolymphopoietic disease was more prevalent in the KrasQ61Rbackground. Loss of theTrp53gene encoding p53 enhances the ability of oncogenic Kras to initiate tumorigenesis in carcinogen and genetic models of lung cancer, while an extra copy ofTrp53(Super p53) was recently shown to suppress Kras-induced tumorigenesis in a genetic model of this disease. Given this, we evaluated whether such an extra copy ofTrp53would alter tumorigenesis upon global activation of a modifiedKrasallele engineered with either a G12D or Q61R mutation. We report that an increase in p53 dosage generally reduced tumor number or grade across a number of organs in a manner largely independent of the type of Kras mutation, which was sufficient to extend lifespan in the less aggressive background of aKrasG12Dinitiating mutation.
Publisher
Cold Spring Harbor Laboratory