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Cathepsin L increased level upon Ras mutants expression: the role of p38 and p44/42 MAPK signaling pathways

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Abstract

The involvement of Ras and three major Ras effectors, Raf, phosphatidylinositol 3-kinase (PI3K) and Ral guanine nucleotide exchange factor in the regulation of lysosomal proteases cathepsin L and B in human fibroblasts was compared. We found that cathepsin L cell content was increased by active Ras overexpression through Raf- and PI3K-mediated signaling pathways, while cathepsin B processing was altered by active Ras overexpression. Cathepsin L increased level following active Ras overexpression correlates with an increase of p38 MAPK activation and content and with an increase of p44/42 MAPK activation, so we investigated the role of these signaling pathways using pharmacological inhibitors. Unexpectedly, the p38 MAPK inhibitor SB203580 produced an increase of cathepsin L content, while the p44/42 MAPK signaling cascade inhibitor U0126 produced a remarkable shift of cathepsin L processing in favor of procathepsin L. In both cases, cathepsin B level and processing were not affected. The analysis of CTSL1 gene transcript demonstrated that cathepsin L protein and transcript correlate both in fibroblasts expressing Ras mutants and in pharmacologically treated cells, thus indicating a transcriptional up-regulation.

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Acknowledgements

This work was supported by COFIN-PRIN, FIRB from “Ministero dell’Istruzione, Università e Ricerca” (Italy) and “Fondazione Cassa di Risparmio di Perugia” (2008.021.375) grants to C.E. Authors disclose any actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence their work.

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  1. Eleonora Sementino & Raffaella Franceschini

    Present address: Cancer Genetics and Signaling Program, Fox Chase Cancer Center, Philadelphia, PA, USA

Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06123, Perugia, Italy

    Lorena Urbanelli, Francesco Trivelli, Luisa Ercolani, Eleonora Sementino, Alessandro Magini, Brunella Tancini, Raffaella Franceschini & Carla Emiliani

  2. Università degli Studi “Guglielmo Marconi”, Rome, Italy

    Raffaella Franceschini

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Correspondence to Carla Emiliani.

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Urbanelli, L., Trivelli, F., Ercolani, L. et al. Cathepsin L increased level upon Ras mutants expression: the role of p38 and p44/42 MAPK signaling pathways. Mol Cell Biochem 343, 49–57 (2010). https://doi.org/10.1007/s11010-010-0497-3

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