Cell expression of a four extra octarepeat mutated PrPC modifies cell structure and cell cycle regulation |
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Authors: | Martín Sergio F Herva María E Espinosa Juan-Carlos Parra Beatriz Castilla Joaquín Brun Alejandro Torres Juan M |
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Affiliation: | Centro de Investigación en Sanidad (CISA-INIA), Ctra. de Algete a El Casar, km. 8.100, 28130 Valdeolmos, Madrid, Spain. |
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Abstract: | RK13 cell lines generated to express bovine PrP(C) with a four extra octarepeat insertional mutation (Bo-10ORPrP(C)) show partially insoluble PrP(C) and lower rates of cell growth when compared to either the same cells expressing wild type Bo-6ORPrP(C) or the original RK13 cell line. The expression of Bo-10ORPrP(C) in cell cultures was also associated with changes in cell size and reorganization of the actin cytoskeleton. This last process was reversed by Clostridium difficile toxin-B, a specific inhibitor of small GTPase proteins. Further, in clones expressing Bo-10ORPrP(C), increased proportions of cells at cell cycle stage G2/M were observed. Proteasome inhibitors caused a further expansion of G2/M-stage cells that was more marked in cell lines expressing Bo-10ORPrP(C) than those expressing Bo-6ORPrP(C), while this effect was minimal or null in the original RK13 cell line. Hence, the presence of Bo-10ORPrP(C) in RK13 cells promotes cell cycle arrest at G2/M, and the effect is amplified by proteasome inhibition. These findings suggest a role for PrP(C) in cell morphology and cell cycle regulation, and open new avenues for understanding the mechanisms underlying PrP mutation-associated diseases. |
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Keywords: | PrPC, cellular prion protein OR, octapeptide repeat Bo-10ORPrPC, bovine PrPC with a four extra octarepeat insertional mutation Bo-6ORPrP, normal Bo-PrPC ORF, open reading frame Tg, transgenic |
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