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Title: The Role of Hsp70 and Nek6 in centrosome clustering in cancer cells
Author: Sampson, Iosifina
ISNI:       0000 0004 6494 4983
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2017
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Mitosis is an important process for the generation of two genetically identical daughter cells. Formation of a bipolar mitotic spindle requires the presence of two centrosomes as these are required to form each pole of the spindle. However, cancer cells, frequently possess extra centrosomes. Therefore, they have developed mechanisms to cluster them into two poles to enable mitotic pseudo-spindle formation and cell survival. Inhibiting centrosome clustering offers a unique and attractive therapeutic approach to selectively kill cells with amplified centrosomes by promoting formation of multipolar spindle poles and mitotic catastrophe. Centrosome clustering mechanisms include proteins with specific roles in microtubule dynamics, microtubule attachments to centrosomes, kinetochores and the cell cortex, as well as the spindle assembly checkpoint. Here, we identify a new pathway that contributes to centrosome clustering and involves the Nek6 kinase and Hsp72 chaperone. Nek6, as well as its upstream activators Plk1 and Aurora-A, targets Hsp72 to the poles of cells with amplified centrosomes. Blocking Hsp72 or Nek6 activity leads to formation of multipolar spindles with poles that always contain centrosomes, whereas other centrosome de-clustering agents trigger formation of acentrosomal poles. Indeed, inhibition of Hsp72 in ALL cells led to an increase of multipolar spindle frequency that correlated with centrosome amplification. Dynein/dynactin and phospho-Hsp72 colocalise to kinetochores and we suggest that they are required for proper attachment of microtubules to kinetochores to facilitate a stable bipolar mitotic spindle and potentially centrosome clustering. Additionally, loss of Hsp72 or Nek6 function did not disrupt either mitotic spindle formation or mitotic progression in non-cancer derived cells versus cancer cells. Hence, the Nek6-Hsp72 pathway, and its potential downstream target dynein, may act as a novel pathway of centrosome clustering that reveals a new opportunity for targeting centrosome clustering and mitotic progression in cancer cells.
Supervisor: Fry, Andrew ; Dyer, Martin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available