Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B.

Abstract

The interleukin-2 (IL-2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus . Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the FK-506-and CsA-sensitive enzyme required for TcR mediated activation of the LL-2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co-stimulus required to activate the IL-2 promoter elements IL-2A (which binds the factors OAP and Oct-i) and LL-2E (which binds NF-AT), and completely substitutes for the Ca2+ co-stimulus required to stimulate an NF-xB-dependent element. Calcineurin stimulates the NF-xB element by enhancing inactivation of IxB/MAD3, an inhibitor of NF-xB, thereby increasing the amount of nuclear NF-xB DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate IxB, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor.

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells

“…Calcineurin is a Ca 2+ /calmodulindependent protein phosphatase involved in various signalling pathways of vesicular trafficking [42]. Notably, inhibitors of calcineurin counteracted the stimulatory effect of inositol hexakisphosphate on endocytosis in insulin-producing cells [43], suggesting that calcineurin might act as a modulator of the endocytotic process in the beta cell.…”

Calcineurin and mitochondrial function in glutamate‐induced neuronal cell death

“…Calcineurin is a Ca2+/ calmodulin-regulated protein phosphatase with broad substrate specificity. Calcineurin substrates that could affect neuronal survival include NOS [22], transcription factors [27,28] and the NMDA receptor itself [29][30][31][32][33]. In this system, the lack of a protective effect of NC-nitro-L-arginine rules out the involvement of endogenous NO production.…”

Inhibitors of NF-κB signaling: 785 and counting

“…Cyclosporin A (CsA), inhibits B-and T-cell proliferation by blocking the activity of calcineurin, a calcium and calmodulin-dependent serine/threonine phosphatase (Frantz et al, 1994). Several reports have shown that CsA can also inhibit NF-kB induction, although the mechanism by which CsA exerts this inhibitory effect may differ in different situations.…”

“…Some inhibit NF-kB nuclear translocation by stabilizing IkBa (Meyer et al, 1997), some may act on NF-kB through inhibiting calcineurin (Frantz et al, 1994), some by binding heatshock proteins (Tepper et al, 1995) and some by modulating the DNA binding or transactivation potential of NF-kB (McCaffrey et al, 1994;Wechsler et al, 1994;Kunz et al, 1995;Qiu et al, 1999).…”