2019_Skalka_GLS_PhD.pdf (12.8 MB)
Molecular characterisation of putative WNT signalling protein, Leucine Zipper and ICAT domain containing (LZIC)
thesisposted on 2020-02-04, 11:37 authored by George L. Skalka
The regulatory events which control cell division are referred to as the cell cycle. The cell cycle is arrested in non-permissive conditions by cell cycle checkpoints. The functioning of these checkpoints in response to stimuli prevents incorporation of mutations and acquisition of aneuploidy, while failure is a promoter of oncogenesis and hyper proliferative disorders. Interestingly, both the development and the treatment of cancer are dependent on the modulation of these checkpoints. Therefore, identification of proteins which regulate these cell cycle checkpoints can both provide mechanistic insight and treatment targets for cancer. Ionising radiation (IR) is a well-established cancer therapy and a potent activator of the cell cycle checkpoints. However, the mechanisms governing cellular response to IR are under investigated compared to many small molecular inhibitors and chemotherapeutic agents. The Leucine zipper and ICAT containing (LZIC) protein is poorly characterised but has been implicated in the development of IR induced tumorigenesis. Interactome analysis of LZIC highlights an enrichment for spliceosome components. In parallel, I show that the transcriptional response of LZIC knock-out cells to IR is altered, with emphasis on MYC signalling and G2/M checkpoint. Analysis of the cell cycle checkpoint activation by flow cytometry and western blot indicate an early release phenotype from the late G2/M checkpoint, with partial recovery of the phenotype being observed following treatment with protein phosphatase inhibitor. In addition, quantification of chromosome number in LZIC KO cell lines shows an increased aneuploidic state. Survival analysis for multiple human cancers shows decreased prognosis of patients with reduced LZIC expression. My findings suggest that LZIC is a new component of the cell cycle regulatory machinery with potential usage as a biomarker for IR cancer therapy sensitivity.
Supervisor(s)Michal Malewicz; Martin Bushell
Date of award2019-12-12
Author affiliationMRC Toxicology Unit
Awarding institutionUniversity of Leicester