JCI online early table of contents: June 1, 2010

Inhibitors of GSK-3 proteins are being developed as potential therapeutics for numerous conditions, including bipolar disorder, Alzheimer disease, and diabetes. However, a team of researchers, led by Thomas Force, at Thomas Jefferson University, Philadelphia, has generated data in mice that indicate that these drugs might have adverse effects on the heart, suggesting that the risk/benefit assessment of such drugs might need to be considered carefully.

In the study, mice lacking GSK-3-alpha were found to develop heart defects when they were analyzed at over 2 months of age. In particular, they had enlarged heart muscle cells and hearts, and their hearts showed an inability to contract optimally. Further, in a model of high blood pressure, which puts substantial stress on the heart, mice lacking GSK-3-alpha developed much more severe heart defects than did normal mice. These and other data generated in the study lead the authors to conclude that in the absence of GSK-3-alpha, the mouse heart cannot respond effectively to high blood pressure and rapidly fails, raising concern that therapeutic GSK-3 inhibitors might have serious adverse effects.

TITLE: GSK-3-alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice

AUTHOR CONTACT:
Thomas Force
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: 215.503.9520; Fax: 215.503.5731; E-mail: thomas.force@jefferson.edu.

View this article at: http://www.jci.org/articles/view/41407?key=94a4420b0090e907f6f6

A team of researchers, led by Valina Dawson and Ted Dawson, at Johns Hopkins University School of Medicine, Baltimore, has now identified the gene regulatory protein NFI-A as a new molecular regulator of nerve cell protection in mice. Such information has implications for developing therapeutics that could provide protection against nerve cell death due to neurologic disorders and stroke.

Sublethal doses of the molecule NMDA induce nerve cells to trigger a molecular survival program. NFI-A is one protein upregulated in this context, but its role in nerve cell survival had not been determined. In this study, knocking down NFI-A induction in mouse nerve cells substantially reduced the neuroprotective effects of sublethal doses of NMDA, indicating a role in the molecular survival program triggered by sublethal doses of NMDA. Several other lines of evidence supported this conclusion and even indicated that NFI-A was required for the protective effects of sublethal doses of NMDA. These data, define NFI-A as a gene regulatory protein central to nerve cell protection.

TITLE: NMDA-induced neuronal survival is mediated through nuclear factor I-A in mice

AUTHOR CONTACT:
Valina L. Dawson
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410.614.3359; Fax: 410.614.9568; Email: vdawson@jhmi.edu.

Ted M. Dawson
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: 410.614.3359; Fax: 410.614.9568; E-mail: tdawson@jhmi.edu.

View this article at: http://www.jci.org/articles/view/33144?key=57a4c559f4f5335c9a48

Promising results have been obtained in clinical trials treating cancer patients with a drug that can activate immune cells known as NKT cells. However, many patients were not eligible for the trial because they did not have sufficient NKT cells in their body. Methods to generate extra NKT cells for a patient are therefore needed. In this regard, a team of researchers, led by Haruhiko Koseki and Masaru Taniguchi, at the RIKEN Research Center for Allergy and Immunology, Japan, has now developed in mice a way to generate lots of NKT cells with antitumor activity.

In the study, large numbers of NKT cells were generated from induced pluripotent stem cells that were themselves derived from structural cells isolated from mice engineered to express the special NKT cell receptor. Importantly, these cells could suppress tumor growth when transplanted into tumor-bearing mice. Furthermore, as NKT cells could also be generated from induced pluripotent stem cells that were themselves derived from NKT cells isolated from the spleens of normal mice, the authors suggest that it might be possible to adapt their protocol to generate large numbers of patient-specific NKT cells with antitumor activity.

TITLE: Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells

AUTHOR CONTACT:
Haruhiko Koseki
RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
Phone: 81.45.503.9689; Fax: 81.45.503.9688; E-mail: koseki@rcai.riken.jp.

Masaru Taniguchi
RIKEN Research Center for Allergy and Immunology, Yokohama, Japan.
Phone: 81.45.503.7001; Fax: 81.45.503.7003; E-mail: taniguti@rcai.riken.jp.

View this article at: http://www.jci.org/articles/view/42027?key=33e68d8dc2fe34df1e69

Treatment for a form of lymphoma known as T-ALL often causes long-term complications, and many patients die from recurrent disease despite therapy. Better understanding of the molecular mechanism underlying disease is needed if improved therapeutics are to be developed. For example, although it is known that activating mutations in the NOTCH1 gene contribute to disease, how they contribute to disease is not known. However, Richard Bram and colleagues, at the Mayo Clinic, Rochester, have now provided new insight into this issue by showing that the protein Hrb is a critical mediator of Notch-induced T-ALL development in mice. As loss of Hrb reduced the incidence or delayed the onset of disease in mouse models of NOTCH1-associated T-ALL, the authors suggest that therapeutics targeting Hrb might help improve the efficacy of current T-ALL therapies or even provide a completely novel treatment approach.

TITLE: HIV-1 Rev–binding protein accelerates cellular uptake of iron to drive Notch-induced T cell leukemogenesis in mice

AUTHOR CONTACT:
Richard J. Bram
College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507.284.2028; Fax: 507.284.3757; E-mail: bramr@mayo.edu.

View this article at: http://www.jci.org/articles/view/41277?key=4a1abb71095793849ea4

Human skin cells known as keratinocytes only live for a short time in culture, making it hard to study skin biology and the mechanisms underlying skin-related diseases. But now, a team of researchers, led by Alison McBride, at the National Institute of Allergy and Infectious Diseases, Bethesda, has identified a way to immortalize human keratinocytes such that they live long-term in culture. Specifically, treating human keratinocytes with a chemical that inhibits ROCK proteins enabled their long-term culture. Importantly, the immortalized cells exhibited the same properties as recently freshly isolated human keratinocytes. The authors hope that not only will this technique help further understanding of keratinocyte biology and skin-related diseases but also have therapeutic and diagnostic impact.

TITLE: Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor

AUTHOR CONTACT:
Alison A. McBride
National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
Phone: 301.496.1370; Fax: 301.451.5330; E-mail: amcbride@nih.gov.

View this article at: http://www.jci.org/articles/view/42297?key=f2c3b0391111c27af8ed

Mutations in the PTEN gene are some of the most commonly detected disease-associated mutations in human cancers, including a leukemia characterized by abnormal expansion of immune cells known as T cells. To study the association between PTEN gene mutations and T cell cancers, mice lacking PTEN in their T cells have been generated. Surprisingly, these mice develop both a T cell lymphoma and an autoimmune disorder characterized by the accumulation of T cells that attack the body. The relationship between these two diseases was not clear. But now, Laurence Turka and colleagues, at the University of Pennsylvania, Philadelphia, have determined that the two diseases are separable and stem from PTEN-mediated defects at different stages of T cell development. Specifically, lymphomas arise from developing T cells in the thymus while autoimmunity arises from mature T cells in the periphery. Further analysis provided more detail of the multiple and distinct regulatory functions of PTEN in the development of T cell lymphomas and autoimmunity.

TITLE: Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice

AUTHOR CONTACT:
Laurence A. Turka
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617.735.2919; Fax: 617.735.2902; E-mail: lturka@bidmc.harvard.edu.

View this article at: http://www.jci.org/articles/view/42382?key=b1a30e964f7e90bcb1e6

Immune cells known as neutrophils have such an important role in immune responses against invading microbes that individuals with neutropenia (i.e., abnormally low numbers of these cells in the blood) are highly susceptible to bacterial infection. Maintaining adequate numbers of neutrophils in the blood, by balancing their release into the blood and their clearance from it, is therefore important. Daniel Link and colleagues, at Washington University School of Medicine, Saint Louis, have now provided new insight into the molecules that regulate the release of mouse neutrophils into the blood.

Neutrophils are made in the bone marrow and stay there until directed to enter the blood. Signaling to neutrophils through their cell surface protein CXCR4 retains them in the blood. Link and colleagues found that signaling to neutrophils through their cell surface protein CXCR2 promotes their release from the bone marrow by opposing CXCR4 signals. Interestingly, in bone marrow chimera studies, neutrophils lacking CXCR2 were preferentially retained in the bone marrow, a characteristic of the congenital disorder myelokathexis, which is characterized by chronic neutropenia, suggesting that mutations in the CXCR2 gene might underlie disease in some patients with this condition.

TITLE: CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow

AUTHOR CONTACT:
Daniel C. Link
Washington University School of Medicine, Saint Louis, Missouri, USA.
Phone: 314.362.8771; Fax: 314.362.9333; E-mail: dlink@dom.wustl.edu.

View this article at: http://www.jci.org/articles/view/41649?key=57962f2347922cc5a44f

Liver cancer is the fifth most common cancer in the world; it carries a poor prognosis. Better understanding of the molecular mechanism underlying the formation of liver cancer is needed if we are to develop new therapeutics. Nikolai Timchenko and colleagues, at Baylor College of Medicine, Houston, have now provided new insight into this by identifying in mice a molecular mechanism that supports the development of liver cancer.

The protein C/EBP-alpha has an important role in keeping liver cells dormant. Modification of C/EBP-alpha such that one of its building blocks is phosphorylated (S193-ph) increases as mice age, as does the incidence of the spontaneous development of tumors in the liver. To determine if the two events were linked, Timchenko and colleagues engineered mice to express a version of C/EBP-alpha that mimics S193-ph in place of the normal C/EBP-alpha. Treatment of these mice with a chemical that induces the formation of liver tumors led to earlier development of tumors than occurs in mice with normal C/EBP-alpha. Further analysis defined the molecular mechanism of this effect, which the authors hope could provide potential therapeutic targets for the prevention of liver cancer.

TITLE: Elimination of C/EBP-alpha through the ubiquitin-proteasome system promotes the development of liver cancer in mice

AUTHOR CONTACT:
Nikolai A. Timchenko
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.1567; Fax: 713.798.4161; E-mail: nikolait@bcm.tmc.edu.

View this article at: http://www.jci.org/articles/view/41933?key=b6bf917c9e9b5a7557cf