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Title: The role of Tiam1/Rac signalling in the centriole cycle
Author: Ogg, Erinn-Lee
ISNI:       0000 0004 5922 8819
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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The mitotic spindle is a structure that facilitates the equal segregation of DNA into two daughter cells during mitosis. The centrosomes organise the mitotic spindle in to a bipolar conformation, and this arrangement is essential for maintaining faithful chromosome segregation. Deviations in centrosome number alter the structure of the spindle and this can promote multipolar cell divisions and large scale aneuploidy. Therefore centrosome number is tightly regulated in normal cells to prevent interference with bipolar spindle assembly and faithful chromosome segregation. Tumour cells often have supernumerary centrosomes. To prevent interference with bipolar spindle assembly extra centrosomes are clustered in to a bipolar spindle arrangement – preventing a multipolar cell division and intolerable levels of aneuploidy. However centrosome clustering can promote lagging chromosomes during anaphase, a major contributor to chromosomal instability. Chromosomal instability has been shown to enhance the malignant potential of tumour cells. Therefore it is important to understand the mechanisms involved in regulating centrosome number and how these become deregulated in cancer. Centrosome number is regulated by the centrioles, small barrel shaped organelles found within the core of the centrosome. We have identified Tiam1, a Rac specific guanine nucleotide exchange factor, as a novel regulator the centriole cycle. Tiam1 knockdown is sufficient to promote the assembly of multiple aberrant centriole structures in human tumour cell lines. These aberrant centriole structures behave like functional centrioles and correlate with an increase in lagging chromosomes at anaphase – suggesting these structures are capable of promoting chromosomal instability in human tumour cell lines. Moreover we have shown that Tiam1 regulates centriole number by preventing centriole re-duplication events and significantly this effect is independent of Rac activation. We have also identified MCM5 as a novel Tiam1 interactor. MCM5 has been identified in the literature as a regulator of centrosome re-duplication. Therefore we propose that Tiam1 and MCM5 co-operate to prevent centriole re-duplication in human tumour cell lines. These findings identify Tiam1 as a potential prognostic marker of centriole amplification and chromosomal instability in human tumours.
Supervisor: Hagan, Iain ; Malliri, Angeliki Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available