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Publication Detail
Heat shock protein 27 is the major differentially phosphorylated protein Involved in renal epithelial cellular stress response and controls focal adhesion organization and apoptosis
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    de Graauw M, Tijdens I, Cramer R, Corless S, Timms JF, van de Water B
  • Publication date:
  • Pagination:
    29885, 29898
  • Journal:
    Journal of Biological Chemistry
  • Volume:
  • Issue:
  • Status:
  • Print ISSN:
  • Keywords:
    Apoptosis, data, Down-Regulation, Electrophoresis, Epithelial Cells, Gel, jun, metabolism, OnCite, Phosphorylation, Proteins, Two-Dimensional
  • Notes:
    Using Smart Source ParsingJun
We used two-dimensional difference gel electrophoresis (2D-DIGE) to determine early changes in the stress response pathways that precede focal adhesion disorganization linked to the onset of apoptosis of renal epithelial cells. Treatment of LLC-PK1 cells with the model nephrotoxicant 1,2-(dichlorovinyl)-L-cysteine (DCVC) resulted in a > 1.5-fold up- and down-regulation of 14 and 9 proteins, respectively, preceding the onset of apoptosis. Proteins included those involved in metabolism, i.e. aconitase and pyruvate dehydrogenase; and those related to stress responses and cytoskeletal reorganization, i.e. cofilin, Hsp27 and alpha-B-crystallin. Most prominent changes were found for Hsp27, which was related to a pI shift in association with an altered phosphorylation status of serine residue 82. Although both p38 and JNK were activated by DCVC, only inhibition of p38 with SB203580 reduced Hsp27 phosphorylation, which was associated with accelerated reorganization of focal adhesions, cell detachment and apoptosis. In contrast, inhibition of JNK with SP600125 maintained cell adhesion as well as protection against apoptosis. Active JNK co-localized at focal adhesions after DCVC treatment in a FAK dependent manner. Inhibition of active JNK localization at focal adhesions did not prevent DCVC-induced phosphorylation of Hsp27. Overexpression of a phosphorylation-defective mutant Hsp27 acted as a dominant negative and accelerated the DCVC-induced changes in the focal adhesions as well as the onset of apoptosis. Our data fit a model whereby early p38 activation results in a rapid phosphorylation of Hsp27, a requirement for proper maintenance of cell adhesion, thus suppressing renal epithelial cell apoptosis.
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