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  • Gupta, Deepesh Kumar, 1990-, et al. (författare)
  • Fate of bi-nucleated cells: the role of septin and Ras
  • 2018
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Integrin-mediated adhesion is required to complete cytokinesis, and failure in the process can generate tetraploid cells, which are potentially oncogenic. The effect of cell detachment on the cytokinesis process and on the following cell cycle was analyzed in the non-transformed human fibroblast cell line BJ and in BJ cells expressing SV40 LT (BJ-LT) +/- an oncogenic Ras mutant. In non-adherent BJ and BJ-LT cells, ALIX could not be recruited to the midbody (MB) and cytokinetic abscission did not occur. Based on the results from several approaches, this block was concluded to be overcome in the detached BJ-LT-Ras cells. Non-adherent BJ and BJ-LT cells maintained the septin-associated intercellular bridge (ICB) formed by cleavage furrow ingression, for more than 24 hours. After re-adhesion to fibronectin most such cells divided by cytofission due to tension exerted on the narrow bridge, while a minor fraction of the cell population instead became bi-nucleated because of regression of the intercellular bridge. Adherent bi-nucleated BJ-LT cells progressed through the cell cycle and at mitosis they divided into two mono-nucleated (4N) cells, while adherent bi-nucleated BJ cells were arrested in the G1 phase and became senescent. Thus, p53-dependent mechanism(s) prevented the formation of tetraploid cells from non-transformed bi-nucleated cells. The two centrosomes in the adherent bi-nucleated cells rapidly fused, indicating that p53 was activated via the PIDDosome mechanism. The results show that several mechanisms contribute to prevent detached normal cells from generating tumor-causing tetraploid cells, and that expression of an activating Ras mutation can promote cytokinesis in detached tumor cells. 
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