SYSTEMS BIOLOGY STUDY OF KIFC1, CENTROSOME AMPLIFICATION AND CELL CYCLE RELATIONSHIPS

Zilinskas, Linas and Fielding, Andrew and O'Shea, Paul (2025) SYSTEMS BIOLOGY STUDY OF KIFC1, CENTROSOME AMPLIFICATION AND CELL CYCLE RELATIONSHIPS. Masters thesis, Lancaster University.

Text (2025LinasZilinskasPhD)
Thesis-LinasZilinskas.pdf - Published Version
Download (2MB)

Abstract

Many cancer cells exhibit the state known as centrosome amplification, where they have more than two centrosomes as they undergo mitosis. In order to cope with centrosome amplification, cells require mechanisms to cluster their amplified centrosomes. KIFC1 is a kinesin that performs the clustering of multiple centrosomes and this function allows survival of cells with centrosome amplification. KIFC1 is best known for its ability to cluster centrosomes, with minor evidence suggestive of some functions in the cell cycle. Meanwhile, the centrosome is well known for its ability to separate chromosomes, receiving much less attention for housing many cell cycle proteins and associated events. Here, the aim was to examine the relationships between the cell cycle, centrosome amplification and KIFC1 function, in particular how centrosome amplification affects the cell cycle lengths and parameters occurring on centrosomes and how KIFC1 affects the lengths of the phases of the cell cycle. The link between KIFC1 and cell cycle lengths and between centrosomes and cell cycle lengths has been investigated and it was found that KIFC1 depletion increases the lengths of G1 phase and the period of the cell cycle from S to Anaphase for both cells with normal and amplified centrosome number. KIFC1 depletion also results into a lower proportional increase of the number of cells in a population over time by 33.5 times. Amplified centrosomes have shown no effect on the length of the cell cycle. To further investigate the effect of centrosomes on the cell cycle, a systemic method has been utilized to identify proteins specific for the cell cycle that could be affected by centrosome amplification, potentially modyfing their cell cycle functions; PLK1, and AURKA, in particular the phosphorylated versions of both. It was found that centrosome amplification affects the amounts and activity of these proteins at centrosomes and disturbs certain relationships between the centrosomal parameters and parameters of these proteins.