http://intl.jci.org/just-published en-us 2008 The American Society for Clinical Investigation http://www.jci.org/icons/banner/rss_title.gif http://content.jci.org Irini Bournazou, John D. Pound, Rodger Duffin, Stylianos Bournazos, Lynsey A. Melville, Simon B. Brown, Adriano G. Rossi, Christopher D. Gregory http://intl.jci.org/articles/view/36226 info:doi/10.1172/JCI36226 American Society for Clinical Investigation Dongki Yang, Nikolay Shcheynikov, Weizhong Zeng, Ehud Ohana, Insuk So, Hideaki Ando, Akihiro Mizutani, Katsuhiko Mikoshiba, Shmuel Muallem http://intl.jci.org/articles/view/36983 3^– secretion are vital functions of secretory epithelia. In most epithelia, this entails HCO₃^– entry at the basolateral membrane, mediated by the Na⁺-HCO₃^– cotransporter, pNBC1, and exit at the luminal membrane, mediated by a CFTR-SLC26 transporters complex. Here we report that the protein IRBIT (inositol-1,4,5-trisphosphate [IP₃] receptors binding protein released with IP₃), a previously identified activator of pNBC1, activates both the basolateral pNBC1 and the luminal CFTR to coordinate fluid and HCO₃^– secretion by the pancreatic duct. We used video microscopy and ion selective microelectrodes to measure fluid secretion and Cl^– and HCO₃^– concentrations in cultured murine sealed intralobular pancreatic ducts. Short interference RNA–mediated knockdown of IRBIT markedly inhibited ductal pNBC1 and CFTR activities, luminal Cl^– absorption and HCO₃^– secretion, and the associated fluid secretion. Single-channel measurements suggested that IRBIT regulated CFTR by reducing channel mean close time. Furthermore, expression of IRBIT constructs in HEK cells revealed that activation of pNBC1 required only the IRBIT PEST domain, while activation of CFTR required multiple IRBIT domains, suggesting that IRBIT activates these transporters by different mechanisms. These findings define IRBIT as a key coordinator of epithelial fluid and HCO₃^– secretion and may have implications to all CFTR-expressing epithelia and to cystic fibrosis. ]]> info:doi/10.1172/JCI36983 American Society for Clinical Investigation Eirini P. Papapetrou, Damian Kovalovsky, Laurent Beloeil, Derek Sant’Angelo, Michel Sadelain http://intl.jci.org/articles/view/37216 + tumors. Hematopoietic mouse chimeras engrafted with a conalbumin-specific TCR prone to thymic clonal deletion acquired peptide-specific T cell responsiveness only when the vector-encoded TCR transcript was similarly engineered to be subject to regulation by miR-181a. These results demonstrate the potential of miRNA-regulated transgene expression in stem cell–based therapies, including cancer immunotherapy. ]]> info:doi/10.1172/JCI37216 American Society for Clinical Investigation