The implication of Kv10.1 in the regulation of G2/M progression

by Naira Movsisyan
Doctoral thesis
Date of Examination:2019-05-16
Date of issue:2020-05-19
Advisor:Dr. Luis A. Pardo
Referee:Dr. Luis A. Pardo
Referee:Prof. Dr. Blanche Schwappach
Persistent Address: http://dx.doi.org/10.53846/goediss-7956

 

 

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Abstract

English

Kv10.1, also termed Eag1 (Ether-a-go-go1), is a voltage gated potassium channel, initially thought to be expressed in the central nervous system. Prolonged or increased expression of Kv10.1 has been found in over 70% of all human tumour tissues, where its presence correlates with poorer prognosis. In peripheral tissues, Kv10.1 is expressed speci fically during the G2/M phase of the cell cycle, and downregulation of the channel extends the G2/M phase duration both in cancer and normal cells. In this project, we elucidate the mechanisms of Kv10.1-mediated regulation at the G2/M phase. We show that Kv10.1 has a dual effect on mitotic microtubule dynamics. It interacts functionally with ORAI1 and through modulation of the cytosolic calcium oscillations changes the microtubule behaviour. Inhibition of either Kv10.1 or ORAI1 conductance stabilises the microtubules. In contrast, siRNA-mediated downregulation of Kv10.1 increases the dynamicity of mitotic microtubules, resulting in a stronger spindle assembly checkpoint, greater mitotic spindle angle, and a decrease in the occurrence of lagging chromosomes. In general, understanding of Kv10.1 modulation of the microtubule architecture will help to find out how exactly a cancer tissue bene fits from the presence of Kv10.1.
Keywords: Kv10.1, cell cycle, G2/M phase, DNA damage activated-checkpoint, spindle assembly checkpoint, microtubule dynamics, ORAI1, calcium.
 
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