Dinamics of Kv10.1 expression through the cell cycle of cancer and non-cancer cells

Dinamics of Kv10.1 expression through the cell cycle of cancer and non-cancer cells

Urrego-Blanco, Diana Elizabeth

Dissertation

Angenommen am: 2014-05-19

Erschienen: 2015-05-12

Betreuer: Pardo, Luis A. Dr.

Gutachter: Stühmer, Walter Prof. Dr.

Gutachter: Moser, Tobias Prof. Dr.

Gutachter: Schild, Detlev Prof. Dr.

Zum Verlinken/Zitieren: http://hdl.handle.net/11858/00-1735-0000-0022-5FDA-E

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Name: PhD_Thesis_Urrego_Blanco.pdf

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Zusammenfassung

Englisch

Kv10.1 is a voltage dependent potassium channel. Its expression has been reported to be widespread in clinical tumors samples of diverse origin. In contrast, expression in normal non-neural tissue has been detected at low levels, and only in restricted populations of cells (Hemmerlein, Weseloh et al. 2006). Kv10.1 is shown to be associated with poor survival, and channel expression also appears to be increased upon mitogen factor stimulation (Borowiec, Hague et al. 2007), favors cell proliferation, and tumor progression (Pardo, del Camino et al. 1999, Weber, Mello de Queiroz et al. 2006, Downie, Sanchez et al. 2008). It is believed that tumor cells expressing Kv10.1 acquire selective advantages that allow them to maintain chronic proliferation. Through this study we identified a dependency of Kv10.1 expression on cell cycle, and a possible mechanism underlying Kv10.1 expression in cancer cells. Kv10.1 is expressed at a defined, narrow time window during G2/M. The Rb/E2F1 pathway regulates its expression time course. Rb/E2F1 complex represses transcription of Kv10.1, and the disruption of the Rb/E2F1 complex by HPV-E7 leads to release of E2F1 transcription factor, which directly binds to Kv10.1pr to activate transcription. Furthermore, we show that in asynchronous HeLa cells, Kv10.1 knockdown increases the G2/M fraction, suggesting that in the absence of Kv10.1 cells spend, on average, more time in G2/M. Finally, taking into account Kv10.1 expression kinetics, we found Kv10.1 expression in normal non-neuronal tissue. A proliferating population of cells located at the bottom and sides of colonic crypts is positive for Kv10.1. These findings can help mechanistically explain the influence of Kv10.1 on tumor cell proliferation and its aberrant expression in tumors. The results reinforce the idea of Kv10.1 as a switch that participates in the regulation, assembly and disassembly of the primary cilium, and therefore controls the exit and entrance into the cell cycle.

Keywords: cell cycle; Kv10.1