PubMed:10358154 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/10358154","sourcedb":"PubMed","sourceid":"10358154","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/10358154","text":"New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation.\nWe had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice. We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors. PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta. PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes. We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and 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