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JCI online early table of contents: Dec. 1, 2008

EDITOR'S PICK: Harnessing miRNA natural gene repressors for anticancer therapy

Michel Sadelain and colleagues, at Memorial Sloan-Kettering Cancer Center, New York, have developed a new approach to modulate the expression of genes for therapeutic purposes, and used this to mediate effective anticancer therapy in mice.

Small, noncoding RNA molecules known as miRNAs are powerful natural repressors of gene expression. In the study, the miRNA miR-181a was harnessed to segregate expression of genes in immune cells known as T cells at different stages of their development. miR-181a is highly expressed in developing T cells, in which it represses expression of many genes, and markedly downregulated in mature T cells. Sadelain and colleagues engineered mouse bone marrow cells to express therapeutic genes only when miR-181a expression is downregulated. These cells were then transplanted into mice and allowed to develop into mature T cells. Expression of the genes (and therefore the proteins made from the genes) was not detected in developing T cells, i.e., when miR-181a was highly expressed, but was detected in mature T cells, i.e., when miR-181a was downregulated. When the genes controlled by miR-181a were responsible for making proteins that target T cells to tumor cells expressing the protein hCD19, the mice that were transplanted with the engineered bone marrow cells were able to reject tumors expressing hCD19. The authors therefore suggest that it might be possible to harness miRNA-regulated therapeutic gene expression in stem cellbased therapies, including cancer immunotherapy.

TITLE: Harnessing endogenous miR-181a to segregate transgenic antigen receptor expression in developing versus post-thymic T cells in murine hematopoietic chimeras

Michel Sadelain
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (212) 639-6190; Fax: (917) 432-2340; E-mail:

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PHYSIOLOGY: The protein IRBIT helps epithelial cells secrete fluid

A number of organs, including the lung, intestine, and pancreas, have glands that secrete fluid and HCO3. Abnormal secretion of fluid and HCO3 can cause disease, including cystic fibrosis and pancreatitis. Shmuel Muallem and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have provided new insight into the molecular mechanisms controlling the secretion of fluid and HCO3 by epithelial cells in the mouse pancreatic duct, data that they hope will have implications for understanding cystic fibrosis.

The authors determined that the protein IRBIT coordinates fluid and HCO3 secretion by epithelial cells in the mouse pancreatic duct through its ability to activate two proteins (pNBC1 and CFTR) that are components of different cell surface complexes involved in the transport of HCO3 into and out of epithelial cells. Activation of pNBC1 is required for HCO3 entry into epithelial cells at the basolateral surface and activation of CFTR is required for HCO3 secretion from epithelial cells at the luminal surface. Further analysis revealed that IRBIT seems to activate these two proteins by distinct mechanisms and that it regulates CFTR by reducing the amount of time the channel is closed. Thus, IRBIT is a key coordinator of a central function of epithelial cells expressing CFTR, the protein that is defective in individuals with cystic fibrosis.

TITLE: IRBIT coordinates epithelial fluid and HCO3 secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct

Shmuel Muallem
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 645-6008; Fax: (214) 645-6049; E-mail:

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PHYSIOLOGY: Lactoferrin explains why apoptotic cell death isn't inflammatory

Cells can die in a number of different ways, including by a form of programmed cell death known as apoptosis. One important aspect of apoptosis is that it does not trigger inflammation. This is in part because the dead cells are rapidly cleared away by cells known as mononuclear phagocytes, rather than phagocytes that are associated with inflammatory responses. Christopher Gregory and colleagues, at Edinburgh University, United Kingdom, have now identified a molecular mechanism that explains why apoptotic cells are cleared away by mononuclear phagocytes, rather than phagocytes associated with inflammatory responses.

In the study, in vitro analysis indicated that numerous apoptotic human cell lines release a soluble factor known lactoferrin, which has previously been shown to have anti-inflammatory properties. Further in vitro analysis revealed that lactoferrin inhibited the migration of phagocytes associated with inflammatory responses but not the migration of mononuclear phagocytes. Similar results were obtained in mice. The authors therefore conclude that lactoferrin has a key role in ensuring that apoptotic cell death is a form of cell death not associated with inflammation through its ability to inhibit the recruitment of phagocytes associated with inflammatory responses.

TITLE: Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin

Christopher D. Gregory
The University of Edinburgh, Edinburgh, United Kingdom.
Phone: 44-131-242-9170; Fax: 44-131-242-9171; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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