EDITOR’S PICK: Intriguing viral link to intestinal cancer in mice
More than 50% of adults in the United States test positive for human cytomegalovirus (HCMV) infection. For most people, infection produces no symptoms and results in the virus persisting in the body for a long time. HCMV infects many cell types in the body including the cells that line the intestines (IECs). New research, led by Sergio Lira, at Mount Sinai School of Medicine, New York, shows that mice engineered to express the HCMV protein US28 in IECs develop intestinal tumors as they age. These mice also develop more tumors than normal mice in a model of inflammation-induced intestinal tumors. The authors therefore suggest that it is possible that HCMV infection could help promote intestinal cancer in humans, although they caution that much more work is needed if such an association is to be confirmed.
TITLE: The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice
AUTHOR CONTACT:
Sergio A. Lira
Mount Sinai School of Medicine, New York, New York, USA.
Phone: 212.659.9404; Fax: 212.849.2525; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/42563?key=dbd641dac08e3962f84a
NEUROBIOLOGY: Breathing kept in rhythm by the protein GlyR-alpha-3
A team of researchers, led by Diethelm Richter, at the University of Göttingen, Germany, has identified a molecular pathway that controls breathing in mice. The team suggests that modulation of this pathway might provide a way to treat breathing disturbances caused by several medical conditions including hyperekplexia (commonly known as startle disease), Rett disease, stroke, deep anesthesia, and opiate abuse.
Rhythmic breathing in mammals is regulated by a network of nerve cells in the lower brainstem. The output of this network is, in turn, controlled by coordinated integration of excitatory and inhibitory inputs. Dysfunction and/or disruption of the inhibitory inputs, such as occurs in hyperekplexia, Rett disease, following stroke, and as a result of deep anesthesia and opiate abuse, leads to suspension of breathing, a condition known as apnea. Inhibitory inputs are largely controlled by proteins known as glycine receptors, and the team identified a molecular mechanism by which the inhibitory glycine receptor alpha-3 subtype (GlyR-alpha-3) is regulated to control breathing in mice. Specifically, activation of the protein serotonin receptor type 1A (5-HTR1A) induced dephosphorylation of GlyR-alpha-3, leading to enhanced inhibition of the nerve cell network controlling rhythmic breathing. As pharmacologic activation of 5-HTR1A protected mice against opiod-induced apnea, the authors suggest that this approach might be of benefit to individuals with some causes of breathing disturbance.
TITLE: Serotonin receptor 1A — modulated phosphorylation of glycine receptor alpha-3 controls breathing in mice
AUTHOR CONTACT:
Diethelm W. Richter
University of Göttingen, Göttingen, Germany.
Phone: 49551.39.5911; Fax: 49551.39.6031; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/43029?key=bc4059475de0954f661d
TUMOR IMMUNOLOGY: Survivin’ anticancer therapy
The protein survivin, which is an inhibitor of a form of cell death known as apoptosis, is overexpressed in many tumors. Several research groups are therefore seeking to develop approaches to direct the immune system to destroy survivin overexpressing cells. One team, led by Dolores Schendel, at Helmholtz Zentrum München, Germany, has now identified a potential problem with this approach.
The team found that human immune cells known as T cells that were engineered to recognize survivin fragments complexed with a protein known as HLA-A2 on the surface of cells were able to kill human tumor cell lines co-expressing HLA-A2 and survivin. However, these cells also killed other T cells in the culture that expressed HLA-A2, because upon activation these T cells expressed survivin, meaning that they started co-expressing HLA-A2 and survivin and became perfect targets for the engineered T cells. The authors fear that this fratricide will limit the anticancer clinical utility of T cells engineered to recognize survivin fragments complexed with HLA-A2.
TITLE: MHC-restricted fratricide of human lymphocytes expressing survivin-specific transgenic T cell receptors
AUTHOR CONTACT:
Dolores J. Schendel
Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.
Phone: 49.89.7099301; Fax: 49.89.7099300; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/43437?key=10fe509dadca2fa340dc
TUMOR IMMUNOLOGY: Turning the immune system on tumor blood vessels benefits mice
The transfer of immune cells known as activated T cells that target tumor proteins has proven beneficial in some individuals with metastatic melanoma, the term given to melanoma skin cancer that has spread to other parts of the body. However, the approach has been harder to tailor to individuals with other forms of cancer because it has been difficult to identify suitable target tumor proteins. Steven Rosenberg and colleagues, at the National Cancer Institute, Bethesda, have now found that mouse T cells engineered to target blood vessels that support tumor growth inhibit the growth of established mouse tumors of different origins (including melanoma, colon cancer, and kidney cancer cell lines). Importantly, this resulted in improved survival. The authors were able to engineer human T cells to target blood vessels in the same way and found that they responded as expected in vitro. Thus, the authors hope that this approach might prove viable for treating a variety of human cancers.
TITLE: Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice
AUTHOR CONTACT:
Steven A. Rosenberg
National Cancer Institute, Clinical Research Center, Bethesda, Maryland, USA.
Phone: 301.496.4164; Fax: 301.402.1738; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/43490?key=63b0a064332e66915306
ONCOLOGY: Cullin 3 provides protection against liver cancer
A team of researchers, led by Nisar Malek, at Hannover Medical School, Germany, has determined that expression of the protein Cul3 is important in preventing liver progenitor cells from becoming liver cancer — initiating cells in mice. These data are likely to have clinical relevance, as loss of Cul3 expression was also detected in human hepatocellular carcinoma samples, the most common form of liver cancer. Importantly, in the human samples, loss of Cul3 expression was associated with de-differentiation of the cells in the tumor, an observation consistent with those made by the team in mouse tumor models. The authors therefore conclude that they have identified a mechanistic framework that explains how highly aggressive liver cancers can arise from liver stem cells.
TITLE: The cyclin E regulator cullin 3 prevents mouse hepatic progenitor cells from becoming tumor-initiating cells
AUTHOR CONTACT:
Nisar P. Malek
Hannover Medical School, Hannover, Germany.
Phone: +49.511.532.4585; Fax: +49.511.532.428; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/41959?key=c48267d19104ffbdbb1f
METABOLIC DISEASE; Nixing NIX puts end to a specific form of diabetes in mice
Individuals who have mutations in one of their two PDX1 genes are highly likely to develop diabetes. Consistent with this, mice with only one functional Pdx1 gene develop diabetes. Two forms of cell death have been linked with the development of diabetes in these mice (apoptosis and necrosis), but how they are triggered by decreased levels of Pdx1 have not been determined. However, Kenneth Polonsky, Gerald Dorn, and colleagues, at Washington University School of Medicine, St. Louis, have now found that increased levels of the protein Nix are key to the apoptosis and programmed necrosis linked to diabetes development in mice with only one functional Pdx1 gene. They therefore suggest that Nix might provide a good target to prevent diabetes in individuals with PDX1 gene mutations.
TITLE: Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic beta-cell death and diabetes
AUTHOR CONTACT:
Kenneth S. Polonsky
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.362.8061; Fax: 314.362.8015; E-mail: [email protected].
Gerald W. Dorn II
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: 314.362.4892; Fax: 314.362.8844; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/44011?key=b240d8e62596e1231a19
MUSCLE BIOLOGY: Local, not global, control of thyroid hormone key in muscle
The active thyroid hormone T3 is a key regulator of skeletal muscle function. A team of researchers, led by Domenico Salvatore, at the University of Naples “Federico II,” Italy, has now determined that local control of T3 levels in mouse skeletal muscle is crucial for proper muscle development and repair, rather than global control of T3 levels by the thyroid gland.
T3 in the body is either secreted from the thyroid gland or generated in the tissues from the precursor hormone T4 by one of two proteins: D1 or D2. The latter is expressed at high levels in skeletal muscle. The team found that mice lacking D2 had normal levels of T3 in their blood but extremely low levels of the hormone in their skeletal muscle and that this was associated with impaired muscle regeneration following injury. Further analysis revealed that the protein FoxO3 was crucial for inducing D2 expression in skeletal muscle. The authors therefore conclude that the FoxO3/D2 pathway allows changes in intracellular T3 levels to be tightly regulated at a cellular level without affecting T3 levels in the blood and other tissues.
TITLE: The Foxo3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration
AUTHOR CONTACT:
Domenico Salvatore
University of Naples “Federico II,” Naples, Italy.
Phone: 39.081.7463780; Fax: 39.081.7463668; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/43670?key=927253bed90bc4dc144e
CARDIOVASCULAR DISEASE: Yet another function for the protein CD36
The protein CD36 has a multitude of functions. A new function can be added to this list thanks to work in mice by a team of researchers led by Roy Silverstein, at the Cleveland Clinic Foundation, Cleveland.
In the study, CD36 was shown to be expressed in mouse arterial blood vessel wall cells known as smooth muscle cells. An absence of CD36 on these cells was associated with increased expression of two antioxidant proteins. This observation was consistent with the decreased levels of reactive oxygen species (molecules that damage cells and tissues) detected in blood vessel walls of mice lacking CD36 after blood vessel wall injury. The authors therefore suggest that targeting CD36 may provide an effective strategy to restore endogenous antioxidant defenses in individuals with blood vessel diseases, a leading cause of death in the United States.
TITLE: CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs
AUTHOR CONTACT:
Roy L. Silverstein
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Phone: 216.444.5220; Fax: 216.444.9404; E-mail: [email protected].
View this article at: http://www.jci.org/articles/view/42823?key=f806d48727b7e074dc84
