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Basiliolides, a class of tetracyclic C19 dilactones from Thapsia garganica, release Ca2+ from the endoplasmic reticulum and regulate the activity of the transcription factors nuclear factor of activated T cells, nuclear factor-kappa B, and activator protein 1 in T lymphocytes

In English

Författare

  • Carmen Navarrete
  • Rocio Sancho
  • Francisco J. Caballero
  • Federica Pollastro
  • Bernd L. Fiebich
  • Olov Sterner
  • Giovanni Appendino
  • Eduardo Munoz

Summary, in English

Calcium concentration within the endoplasmic reticulum ER) plays an essential role in cell physiology. We have investigated the effects of basiliolides, a novel class of C19 dilactones isolated from Thapsia garganica, on Ca2+ mobilization in T cells. Basiliolide A1 induced a rapid mobilization of intracellular Ca2+ in the leukemia T-cell line Jurkat. First, a rapid calcium peak was observed and inhibited by 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester. This initial calcium mobilization was followed by a sustained elevation, mediated by the entry of extracellular calcium through store-operated calcium release-activated Ca2+ (CRAC) channels and sensitive to inhibition by EGTA, and by the CRAC channel inhibitor N-{4-[3,5-bis(trifluoromethyl)-1Hpyrazol1-yl] phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP-2). Basiliolide A1 mobilized Ca2+ from ER stores, but in contrast to thapsigargin, it did not induce apoptosis. Basiliolide A1 induced nuclear factor of activated T cells 1 dephosphorylation and activation that was inhibited by BTP-2 and cyclosporine A. In addition, we found that basiliolide A1 alone did not mediate IKB alpha degradation or RelA phosphorylation (ser536), but it synergized with phorbol 12-myristate 13-acetate to induce a complete degradation of the nuclear factor-KB inhibitory protein and to activate the c-Jun NH2-terminal kinase. Moreover, basiliolide A1 regulated both interleukin-2 and tumor necrosis factor-alpha gene expression at the transcriptional level. In basiliolide B, oxidation of one of the two geminal methyls to a carboxymethyl group retained most of the activity of basiliolide A1. In contrast, basiliolide C, where the 15-carbon is oxidized to an acetoxymethine, was much less active. These findings qualify these compounds as new probes to investigate intracellular calcium homeostasis.

Publiceringsår

2006

Språk

Engelska

Sidor

422-430

Publikation/Tidskrift/Serie

Journal of Pharmacology and Experimental Therapeutics

Volym

319

Issue

1

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Pharmacology and Experimental Therapeutics

Ämne

  • Organic Chemistry

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1521-0103