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15-Deoxy-Δ12,14-prostaglandin-J2 reveals a new pVHL-independent, lysosomal-dependent mechanism of HIF-1α degradation

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL) and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) accumulate HIF-1α in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We found that 15d-PGJ2 induced an over-accumulation of HIF-1α in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain them. We have identified a new lysosomal-dependent mechanism of HIF-1α degradation as a target for 15d-PGJ2 based on: (1) HIF-1α colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ2 inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation of HIF-1α in 15d-PGJ2-treated cells. Therefore, expression of HIF-1α is also modulated by lysosomal degradation.

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Acknowledgments

This work was supported by grants SAL-0311-2006 from the Comunidad de Madrid, SAF2008-01767 from the Spanish Ministerio de Ciencia e Innovación and CCG08-UAH/BIO-4102 from University of Alcala.

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Authors and Affiliations

  1. Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, 28471, Alcalá de Henares, Madrid, Spain

    Gemma Olmos & Javier Lucio-Cazaña

  2. Departamento de Biología Celular y Genética, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    María I. Arenas

  3. Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain

    Raquel Bienes, María Jose Calzada, Julián Aragonés & Manuel O. Landazuri

  4. Departamento de Patología, Hospital Universitario Ramon y Cajal, Madrid, Spain

    Maria Laura Garcia-Bermejo

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  1. Gemma Olmos
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  8. Javier Lucio-Cazaña
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Correspondence to Javier Lucio-Cazaña.

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Olmos, G., Arenas, M.I., Bienes, R. et al. 15-Deoxy-Δ12,14-prostaglandin-J2 reveals a new pVHL-independent, lysosomal-dependent mechanism of HIF-1α degradation. Cell. Mol. Life Sci. 66, 2167–2180 (2009). https://doi.org/10.1007/s00018-009-0039-x

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