Involvement of calcineurin in apoptosis induced by microtubule dysfunction

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Taxol binds to microtubules and induces apoptosis of various cancer cells. Several lines of evidence indicate that taxol induces apoptosis through activation of c-Jun N-terminal kinase (JNK) and the concomitant phosphorylation of B-cell leukemia/lymphoma-2 (Bcl-2) by the activated JNK. Calcineurin is a serine/threonine protein phosphatase and has been reported to be involved in dephosphorylation of Bcl-2. We found that T24 cells derived from human urinary bladder cancer were resistant to taxol. A combination treatment with taxol and cyclosporin A (CsA) or FK506, calcineurin inhibitors, resulted in loss of calcineurin activity and enhancement of phosphorylation of Bcl-2. In addition, treatment of the cells with CsA or FK506 significantly decreased the expression of Bcl-2 at both the protein and mRNA levels. Interestingly, apoptosis of T24 cells was induced by low of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic concentration of taxol in the presence of CsA or FK506. These results suggest that calcineurin has antiapoptotic actions via the dephosphorylation of Bcl-2 and the induction of the gene expression of Bcl-2. In neurons, tau protein binds to microtubules and regulates the microtubule functions in axons. We found that Ca^<2+>, calmodulin-dependent protein kinase II (CaM kinase II) phosphorylated tau at tubulin binding sites and inhibited the binding of tau to microtubules. These results may suggest that CaM kinase II is involved in apoptosis via the phosphorylation of tau.