A mouse model for cyclin E-dependent genetic instability and tumorigenesis

Summary tination of murine cyclin E is triggered by phosphorylation on threonine 393. Cyclin ET393A knockin mice exhibited increased cyclin E stability, but no phenotypic abnormalities. Importantly, loss of the p53 pathway exacerbated the effect of the T393A mutation. Thus, in p21−/− cells the T393A mutation had an exaggerated effect on cyclin E abundance and its associated kinase activity, which caused abnormal cell cycle progression, and genetic instability involving chromosome breaks and translocations. Moreover, cyclin ET393A acted synergistically with p53 deficiency to accelerate tumorigenesis in cyclin ET393A p53−/− mice; Ras more readily transformed cyclin ET393A p53−/− cells than p53−/− cells in vitro; and cyclin ET393A mice had a greatly increased susceptibility to Ras-induced lung cancer.