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- 저자 : Limzerwala, Jazeel Firdos (검색결과 1 건)
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Limzerwala, Jazeel Firdos ProQuest Dissertations & Theses College of Medicin 2020 해외박사(DDOD)
Chromosomal Instability (CIN), the condition where cells constantly mis-segregate their chromosomes in mitosis, is a widely recognized hallmark of human cancers. CIN is now beginning to be recognized as an important source of intra-tumor heterogeneity that can drive disease progression, metastasis, relapse and patient death. It is therefore imperative to fully understand how is CIN engendered and how does it impact different stages of tumorigenesis, to better advance patient care and diagnosis. In the work presented in this thesis, involving several genetically engineered mice strains, we uncover a novel tumor suppressive function for the transcription factor FoxM1 that is independent of its transcriptional ability, identify deregulations in the actomyosin cortex as a driver of CIN and provide preliminary proof-of-concept that CIN drives tumor progression and metastasis. Using genetically engineered mice that express low amounts of FoxM1, we found that FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling, resulting in increased cortical actin density that impedes centrosome separation and predisposes cells to increased incidence of CIN and tumor formation. Re-expression of the FoxM1 Nterminal Domain (NTD) in FoxM1 insufficient mice restores proper control over cortical actin nucleation, mitotic chromosome segregation and tumor suppression, providing evidence for a causal role for increased cortical actin density in driving CIN and tumorigenesis. Our work has also identified the mechanism of how overexpression of Cyclin E1 can predispose mice to hepatocellular carcinoma, which can have far reaching impacts for patients infected with Hepatitis B/C virus or Adeno-associated virus 2, which integrate into the CCNE1 gene locus in humans and cause its overexpression. Collectively, the work presented in this thesis has advanced our understanding of the role of CIN in tumor development.
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