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JCI table of contents: Nov. 15, 2007

EDITOR'S PICK: CD200 stifles antitumor immunity

The prognosis for individuals with metastatic melanoma (MM) is not good. Therapeutic strategies to enhance the immune response have some clinical benefit; however, most patients eventually succumb to progressive disease, in part because their immune cells known as dendritic cells (DCs) fail to sustain an effective antitumor T cell immune response. New data generated in vitro using human melanoma cell lines and resected tumors by Norman Sharpless and colleagues at the University of North Carolina School of Medicine, Chapel Hill, has identified one mechanism that represses DC function in MM.

Expression of CD200 mRNA and protein was found to be higher in resected human melanomas than in other solid tumors. Further analysis revealed that expression of CD200 was regulated by the N-RAS/B-RAF/MEK/ERK MAP kinase signaling pathway, which is aberrantly activated in approximately 80% of individuals with MM. In vitro analysis indicated the potential functional significance of high levels of CD200 expression it enabled melanoma cell lines to repress activation of antitumor T cell immune responses by DCs. The authors therefore suggested that targeting the interaction between CD200 and its receptor might provide a new strategy for the treatment of MM.

TITLE: CD200 is induced by ERK and is a potential therapeutic target in melanoma

Norman E. Sharpless
University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Phone: (919) 966-1185 or (919) 966-4067; Fax: (919) 966-8212; E-mail:

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EDITOR'S PICK: ClC-1 helps mice get a move on

In addition to the progressive muscle weakness and degeneration common to all forms of muscular dystrophy, patients with the most common form of muscular dystrophy affecting adults, myotonic dystrophy type 1 (DM1), also experience an inability to voluntarily relax the muscles (a problem known as myotonia). DM1 originates from complex genetic mutations that result in abnormalities of the muscle proteins, including the muscle-specific chloride channel ClC-1.

Working under the theory that abnormal inclusion of a region of the ClC-1 gene known as exon 7a in the ClC-1 mRNA (the intermediate between gene and protein) may play a role in the development of DM1, Charles Thornton and his colleagues at the University of Rochester, Rochester, discovered a powerful method of correcting this aberrant exon 7a inclusion and reversing myotonia in mouse models of DM1. A nucleic acid compound known as a morpholino antisense oligonucleotide was generated that would allow the muscle cells to skip over the erroneously included exon7a. When this compound was injected into mice with DM1-like disease, exclusion of the extra genetic segment in the ClC-1 mRNA restored the function of ClC-1 protein and eliminated myotonia in the mice. The authors therefore suggested that it might be possible to use this approach to treat myotonia in individuals with DM1.

TITLE: Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

Charles A. Thornton
University of Rochester, Rochester, New York, USA.
Phone: (585) 275-2542; Fax: (585) 273-1255; E-mail:

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GASTROENTEROLOGY: A gut reaction to infection

To ensure that the gut absorbs as many as possible of the nutrients that we consume tiny finger-like structures known as villi protrude from the lining of the gut to increase its absorptive surface area. Continuous turnover of the cells lining the gut is required for it to function optimally. As cells at the tips of the villi naturally die off they are replaced by cells that have migrated to their new home from the base of the villi. Similarly, repair of intestinal injury, which often accompanies traumatic stress, occurs through migration of healthy intestinal cells to the site of injury from the base of the villi. MFG-E8 is a component of human breast milk that protects infants from intestinal infection. It is also known that the MFG-E8 gene is expressed in the adult gut, but its role there has not been well understood. In a new study, Xiao-Di Tan and colleagues at the Northwestern University Feinberg School of Medicine, Chicago, have identified a crucial role for MFG-E8 in maintenance and repair of the murine intestinal lining.

In a wound-healing experiment with cultured rat intestinal epithelial cells, treatment with MFG-E8 improved cell migration to the site of injury. Additionally, depletion of this protein in mice resulted in decreased intestinal cell migration and localized injury of the intestinal lining. Finally, in septic mice with widespread infection due to puncture of the large intestine, treatment with MFG-E8 improved intestinal cell migration, whereas depletion of MFG-E8 prolonged healing time. These data led the authors to suggest that MFG-E8 might be useful for the treatment of individuals with bowel injuries.

TITLE: Milk fat globuleEGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium


Xiao-Di Tan
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Phone: (773) 755-6380; Fax: (773) 755-6581; E-mail:

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IMMUNOLOGY: Sensing bacteria in the gut keeps inflammation at bay

New data generated in mice by Andrew Gewirtz and colleagues at Emory University, Atlanta, has provided support for the hypothesis that defects in the innate immune system might underlie some cases of inflammatory bowel disease a group of disorders characterized by inflammation in the intestine.

In the study, mice lacking a protein known as TLR5 (which senses the bacterial protein flagellin and initiates a proinflammatory response) were found to spontaneously develop inflammation of the colon (colitis), whereas normal mice did not spontaneously develop this disease. Just prior to the onset of spontaneous colitis increased numbers of bacteria were detected in the colon, as were very high levels of proinflammatory mediators. The latter observation was surprising given that TLR5-deficient mice lack an immune sensor of bacterial flagellin. However, consistent with the authors idea that this increased proinflammatory response was induced by other sensors of bacterial products, mice lacking TLR4 and TLR5 did not develop colitis. These data indicate that a deficiency in an immune sensor of bacteria can lead to an increased inflammatory response in the intestine of mice.

TITLE: Deletion of TLR5 results in spontaneous colitis in mice

Andrew T. Gewirtz
Emory University, Atlanta, Georgia, USA.
Phone: (404) 712-9885; Fax: (404) 727-8538; E-mail:

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PULMONARY: Uncovering the mechanisms underlying lung scarring

Pulmonary fibrosis is an incurable disease where the lung becomes scarred due to pathologic accumulation of fibrous scar tissue. Telomerase is a protein most notable for its connections to aging and cancer, but it has also been shown to have increased activity in mice with lung fibrosis. New evidence provided by Sem Phan and colleagues from the University of Michigan Medical School, Ann Arbor, has identified a role for telomerase in the progression of this disease in mice.

Telomerase activity is dependent on the presence of a related protein named TERT. The authors studied the effect of this enzyme in mice with induced lung injury and subsequent fibrosis. They found that mice with reduced TERT levels also had reduced telomerase activity in the lungs, and less severe lung fibrosis. This effect was reversed if the TERT-deficient mice were transplanted with TERT-sufficient bone marrow cells prior to lung injury. Conversely, when normal mice received bone marrow cells from TERT-deficient donors, subsequent telomerase activity and fibrosis of the lung was reduced. From these results, the authors concluded that bone marrow cells expressing TERT are important in the development of pulmonary fibrosis.

TITLE: Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Sem H. Phan
University of Michigan Medical School, Ann Arbor, Michigan, USA.
Phone: (734) 647-8153; Fax: (734) 615-2331; E-mail:

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ONCOLOGY: Breast cancer SK(i)P(s)2 the beat

Increased expression of the gene SKP2 has been detected in nearly 50% of breast cancer cases. New data generated by a team of researchers at the University of Michigan, Ann Arbor, has identified the protein FOXP3 as a suppressor of tumor growth promoted by SKP2, leading the team to suggest that defects in the FOXP3 gene that decrease FOXP3 protein expression might cause SKP2 upregulation and subsequent tumor development.

In the study, mammary tumors from mice expressing decreased amounts of FOXP3 were found to have increased amounts of SKP2. Further, in human breast cancer cell lines overexpression of FOXP3 decreased SKP2 levels, whereas knockdown of FOXP3 expression increased SKP2 levels. Additional analysis indicated that downregulation of SKP2 expression was essential for FOXP3 to inhibit the growth of human breast cancer cell lines lacking expression of HER2, another protein that stimulates tumor development. Together, these data led the authors to conclude that FOXP3 is a suppressor of tumor development induced by SKP2.

TITLE: FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2

Yang Liu
University of Michigan, Ann Arbor, Michigan, USA.
Phone: (734) 615-3158; Fax: (734) 763-2162; E-mail:

Pan Zheng
University of Michigan, Ann Arbor, Michigan, USA.
Phone: (734) 615-3158; Fax: (734) 763-2162; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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