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The effects of Mad2 over-expression on murine lung tumorigenesis

Libouban, Marion

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Abstract

Sixty-eight percent of human solid tumors are aneuploid, which is classically associated with poor patient prognosis. Several mouse models disturbing the spindle assembly checkpoint (SAC) have been developed to study the consequences of chromosome instability (CIN) and aneuploidy in vivo. Current knowledge suggests that aneuploidy can promote tumorigenesis or act as a tumor suppressor. Mad2 is found over-expressed in human tumors, and Mad2 over-expression in mice induces the development of aneuploid tumors and facilitates KrasG12D lung tumor relapse. A proposed mechanism of tumor acceleration by CIN is the facilitation of tumor suppressor loss of heterozygosity. In how far Mad2 over-expression influences Kras driven lung tumorigenesis in a p53 heterozygous background, remains hitherto unclear. In this thesis, I show that Mad2 over-expression increases p53(+/–);KrasG12D mice survival by delaying tumor initiation and progression. Different tumor populations (expressing low, intermediate and high levels of Mad2) have co-evolved from an original population of Mad2-expressing type 2 pneumocytes. My data suggest that high Mad2-expressing lung nodules are selected against during early tumorigenesis and are mainly composed of instable aneuploid cells. Using time-lapse microscopy on mouse embryonic fibroblasts, I analyzed the effect of Mad2 over-expression in the context of p53 heterozygosity. Upon Mad2 over- expression, the inactivation of one copy of p53 rescued mitotic cell death by inducing mitotic slippage and polyploid cells. In vivo, high Mad2 levels impaired S phase entry in tumor cells. Moreover, p53(+/– )KM high nodules strongly induced p21 in a p53-dependent manner. This data suggests that one copy of p53 can induce G1 cell cycle arrest in tumors. Although Mad2 over- expression generates aneuploidy, it does not accelerate p53 loss of heterozygosity (LOH), since Mad2 down-regulation occurs prior to LOH. Importantly, Mad2 over- expression together with p53 heterozygosity also delayed EFGRL858R-induced lung cancer.

Item Type: Dissertation
Supervisor: Gross, Dr. Cornelius
Place of Publication: Heidelberg, Germany
Date of thesis defense: 12 May 2015
Date Deposited: 27 Jul 2015 07:52
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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