FK506 sensitizes mammalian cells to high osmolarity by modulating p38 MAP kinase activation.
The immunosuppressants tacrolimus (FK506) and cyclosporin A (CsA) have increased the survival rates in organ transplantation. Both drugs inhibit the protein phosphatase calcineurin (CaN) in activated T cells, exhibiting similar side-effects. Diabetes is observed more often in FK506 than CsA therapy, probably due to inhibition of new molecular targets other than CaN. We studied FK506 toxicity in mammalian cells. FK506, but not CsA, regulated p38 activation by osmotic stress, and decreased viability in osmostressed cells. In addition, FK506 treatment strongly increased the phosphorylation of the eukaryotic initiation factor-2alpha (eIF-2alpha) subunit. eIF-2alpha phosphorylation, p38 inhibition and cell lethality were relieved by addition of excess amino acids to the medium, suggesting that amino acid availability mediated FK506 toxicity. Therefore, these FK506-dependent responses could be relevant to the non-therapeutic effects of FK506 therapy.
Sanchez-Perez
I
I
Instituto de Investigaciones Biomédicas (CSIC), Madrid, Spain.
Rodriguez-Hernandez
C J
CJ
Manguan-García
C
C
Torres
A
A
Perona
R
R
Murguía
J R
JR
D019703:Calcineurin / Q000378:metabolism / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation / Q000187:drug effects; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013012:Sorbitol / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D015852:Eukaryotic Initiation Factor-2; D007166:Immunosuppressive Agents; D029701:Saccharomyces cerevisiae Proteins; D013012:Sorbitol; D016572:Cyclosporine; D014364:Tryptophan; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D016559:Tacrolimus