JCI online early table of contents: Aug. 15, 2011

Type 2 diabetes is an extremely common chronic condition characterized by high levels of sugar in the blood as a result of either insufficient production of the hormone insulin or an inability of cells to respond to insulin. A combination of genetic and environmental factors causes an individual to develop type 2 diabetes. Among the most reproducible genetic variations associated with type 2 diabetes in different ethnic populations are those in the CDKAL1 gene. However, the mechanisms underlying these associations have not yet been determined. But now, a team of researchers, led by Kazuhito Tomizawa, at Kumamoto University, Japan, has generated evidence in mice that could potentially explain why individuals carrying certain variants of the CDKAL1 gene are at increased risk of developing type 2 diabetes. Specifically, the team found that lack of the Cdkal1 protein led to misreading of certain parts of the gene that produces insulin, a process known as decoding infidelity, and thereby to both decreased insulin production and impaired functioning of insulin-producing cells.

TITLE: Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice

AUTHOR CONTACT:
Kazuhito Tomizawa
Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Phone: 81.96.373.5050; Fax: 81.96.373.5052; E-mail: tomikt@kumamoto-u.ac.jp.

View this article at: http://www.jci.org/articles/view/58056?key=674d43cc7648193d7f39

The main cause of death in women with breast cancer is spread of the original tumor to distant sites, a process known as metastasis. Immune cells known as NK cells help limit tumor progression and metastasis in animal models. But now, a team of researchers, led by Emilie Mamessier and Daniel Olive, at INSERM UMR 891, France, has found that NK cells have a similar role in women with breast cancer, since dysfunction of these cells accompanies breast tumor progression in humans. Interestingly, the team also found that invasive breast tumors have modulated their environment in order to evade the antitumor activity of NK cells. The team therefore suggests that therapies designed to restore NK cell antitumor activity could be of benefit to individuals with breast cancer.

TITLE: Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity

AUTHOR CONTACT:
Emilie Mamessier
INSERM UMR 891, Marseille, France.
Phone: 33.491.758.415; Fax: 33.491.260.364; E-mail: mamessier@ciml.univ-mrs.fr.

Daniel Olive
INSERM UMR 891, Marseille, France.
Phone: 33.491.758.415; Fax: 33.491.260.364; E-mail: daniel.olive@inserm.fr.

View this article at: http://www.jci.org/articles/view/45816?key=11b8f1618b972ab9d324

Merkel cell carcinoma (MCC) is a rare but aggressive form of skin cancer. It was recently found that most cases of MCC are caused by Merkel cell polyomavirus (MCV). However, the mechanisms by which this virus causes MCC are unknown. Insight into this has now been provided by the work of Patrick Moore, Yuan Chang, and colleagues, at the University of Pittsburgh, Pittsburgh, who found that the MCV protein sT is required for tumor cell growth. Detailed analysis by these researchers outlined the molecular mechanism by which MCV sT contributes to MCC and led them to suggest that MCV sT has potential as a diagnostic marker and therapeutic target for MCC.

TITLE: Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator

AUTHOR CONTACT:
Patrick S. Moore
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Phone: 412.623.7721; Fax: 412.623.7715; E-mail: psm9@pitt.edu.

Yuan Chang
University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Phone: 412.623.7721; Fax: 412.623.7715; E-mail: yc70@pitt.edu.

View this article at: http://www.jci.org/articles/view/46323?key=833ffcd40ef4d172008a

Streptococcus pneumoniae is a bacterium that is often found in the human upper respiratory tract (URT). Although it does us no harm in the URT, our immune system works to gradually clear the bacterium, which later returns to start the cycle over again. If we have flu, S. pneumoniae can sometimes overwhelm the host defense system of the URT and reach the lower airways, causing secondary pneumococcal pneumonia, which accounts for much of the increased morbidity and mortality during seasonal and pandemic flu. Two papers from the laboratory of Jeffery Weiser, at the University of Pennsylvania School of Medicine, Philadelphia, provide new insight, gleaned in mice, into the mechanisms of host defense in the airway and how concurrent infection with influenza virus and S. pneumoniae can dysregulate this system. These data could help explain the higher rates of disease associated with influenza virus and S. pneumoniae co-infection in humans.

TITLE: Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice

AUTHOR CONTACT:
Jeffrey N. Weiser
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.3511; Fax: 215.573.4856; E-mail address: weiser@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/57761?key=203bf6033ac7f932881e

ACCOMPANYING ARTICLE
TITLE: Synergistic stimulation of type I interferons during influenza virus coinfection promotes Streptococcus pneumoniae colonization in mice

AUTHOR CONTACT:
Jeffrey N. Weiser
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.3511; Fax: 215.573.4856; E-mail address: weiser@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/57762?key=0a919790aa4c6ff380d9

Osteoporosis, rheumatoid arthritis, bone cancers, and rare clinical disorders such as Nasu-Hakola disease are all characterized by excessive bone loss. Cells known as osteoclasts are responsible for the erosion of the mineralized bone matrix that results in such bone loss. The molecular pathways that control the formation of osteoclasts are only partly defined; new insight into these could provide new therapeutic targets for the treatment of bone diseases characterized by excessive bone loss. In this context, a team of researchers — led by Alexander Barrow, at the University of Cambridge, United Kingdom; and Yongwon Choi, at the University of Pennsylvania School of Medicine, Philadelphia — has now determined that signaling triggered by binding of the protein OSCAR to matrix components known as collagen helps stimulate the generation of mouse and human osteoclasts. The clinical relevance of these data are highlighted by previous studies indicating that OSCAR expression is upregulated in rheumatoid arthritis and that a specific variation in the regulatory region of the OSCAR gene is associated with low bone mineral density in postmenopausal women.

TITLE: OSCAR is a collagen receptor that costimulates osteoclastogenesis in DAP12-deficient humans and mice

AUTHOR CONTACT:
Alexander David Barrow
University of Cambridge, Cambridge, United Kingdom.
Phone: +44.1223.330248; Fax: +44.1223.333875; E-mail: adb44@cam.ac.uk.

Yongwon Choi
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.746.6404; Fax: 215.573.0888; E-mail: ychoi3@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/45913?key=a327042a920cb81d9b29

A team of researchers, led by Min-Liang Kuo, at National Taiwan University Hospital, Taiwan, has generated new insight into the molecular regulation of the tumor-forming capacity of breast cancer cells. These data provide potential new therapeutic targets.

Small, noncoding RNA molecules known as miRNAs are powerful repressors of gene expression. As such they have a key role in many biological processes, including cancer. In this context, the miRNA let-7 acts to suppress tumor development. In this study, Kuo and colleagues found that another miRNA, miR-107, negatively regulates expression of let-7 in human cancer cell lines via direct interaction. Further evidence of the clinical significance of this was provided by the observation that miR-107 is highly expressed in cancerous tissue from patients with advanced breast cancer. These data identify miR-107 as having a role in the promotion of tumor development and suggest it could be a new target for the treatment of breast cancer.

TITLE: MiR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans

AUTHOR CONTACT:
Min-Liang Kuo
National Taiwan University Hospital, Taipei, Taiwan.
Phone: 886.2.2312.3456.88607; Fax: 886.2.2341.0217; E-mail: kuominliang@ntu.edu.tw.

View this article at: http://www.jci.org/articles/view/45390?key=cfce7e03b8b196ce0c46

Hirschsprung (HSCR) disease is a relatively common complex genetic disorder, affecting 1:5,000 newborns. The mechanisms underlying the development of HSCR are not well understood. A team of researchers, led by Elly Ngan, at University of Hong Kong, China, has now generated data that lead them to suggest a new disease mechanism for HSCR.

Individuals with HSCR develop a blockage of the large intestine due to an inability of the muscles in the wall of the large intestine to contract. Nerves trigger the muscles in the wall of the large intestine to contract but individuals with HSCR lack nerve cells in part or all of the large intestine. This has been attributed to a failure of enteric neural crest cells (ENCC) to form bundles of nerve cells (ganglia) in the hindgut during development. The human genetic analysis reported by Ngan and colleagues indicates that specific constellations of PTCH1 gene (which templates a protein in the Hedgehog signaling pathway) and DLL3 gene (which templates a protein in the Notch signaling pathway) variants confer higher risk of HSCR. Further analysis in genetically modified mice indicated that the Hedgehog and Notch signaling pathways interact to control ENCC generation of nerve cells and glial cells (support cells of the nervous system). The data further suggest that dysregulation of the system can lead to Hedgehog/Notch-induced premature generation of glial cells and that this may represent a new disease mechanism for HSCR.

TITLE: Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans

AUTHOR CONTACT:
Elly S.W. Ngan
University of Hong Kong, Hong Kong, China.
Phone: 852.2819.9631; Fax: 852.2816.9621; E-mail: engan@hku.hk.

View this article at: http://www.jci.org/articles/view/43737?key=b1ccc04aef76bf1dc05a

The proteasome is a protein complex that degrades abnormal proteins in a cell and controls the turnover of normal proteins. Proteasome functional insufficiency has been observed in the hearts of patients with a range of heart diseases, including desmin-related cardiomyopathy, and implicated in many common deleterious events in the heart, including the damage to the heart muscle cells that occurs after a heart attack (myocardial I/R injury). A team of researchers, led by Xuejun Wang, at the University of South Dakota, Vermillion, has now shown that enhancing the proteolytic function of the proteasome in mouse heart muscle cells provides benefit in a well-established model of desmin-related cardiomyopathy and in mice with myocardial I/R injury. Future studies will further investigate the therapeutic potential of manipulating proteasomal activity in heart muscle cells.

TITLE: Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice

AUTHOR CONTACT:
Xuejun Wang
Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota, USA.
Phone: 605.677.5132; Fax: 605.677.6381; E-mail: Xuejun.Wang@usd.edu.

View this article at: http://www.jci.org/articles/view/45709?key=4fb0f7b1f904b0cce02c