[ Back to EurekAlert! ] Public release date: 28-Dec-2009
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Contact: Karen Honey
Journal of Clinical Investigation

JCI table of contents: Dec. 28, 2009

EDITOR'S PICK: 'Notch'ing up a role in the multisystem disease tuberous sclerosis complex

Two independent teams of researchers have identified a role for enhanced activation of the signaling protein Notch in tumors characterized by inactivation of either the TSC1 or the TSC2 protein. As indicated by Warren Pear, at the University of Pennsylvania, Philadelphia, in an accompanying commentary, these data provide a rationale for testing whether Notch inhibitors are of benefit to those with TSC-associated tumors.

Tuberous sclerosis complex (TSC) is a multisystem disease characterized by the formation of benign tumors in multiple organs. It is caused by mutations in either the TSC1 or TSC2 gene. In the first study, Elizabeth Petri Henske, at Brigham and Women's Hospital, Boston, and Fabrice Roegiers, at Fox Chase Cancer Center, Philadelphia, found evidence of Notch signaling pathway activation in human angiomyolipomas, benign kidney tumors often found in patients with TSC, and in an angiomyolipoma-derived cell line. Importantly, inhibition of Notch suppressed proliferation of TSC2-deficient rat cells in a xenograft model. These authors therefore conclude that TSC proteins regulate Notch activity and that Notch dysregulation may underlie some of the distinctive clinical and pathologic features of TSC.

Results presented in the second study, by Hongbing Zhang and colleagues, at the Chinese Academy of Medical Sciences and Peking Union Medical College, People's Republic of China, provide further evidence that TSC proteins regulate Notch activity and that Notch overactivity contributes to the tumorigenic potential of cells deficient in either TSC1 or TSC2.

TITLE: The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development

Elizabeth Petri Henske
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Phone: (617) 355-9049; Fax: (617) 355-9016; E-mail: Ehenske@partners.org.

Fabrice Roegiers
Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Phone: (215) 728-5518; Fax: (215) 214-2412; E-mail: Fabrice.Roegiers@fccc.edu.

View this article at: http://www.jci.org/articles/view/40221?key=76V59G6WkmwhlzpC43Dd

TITLE: Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade

Hongbing Zhang
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Phone: 01186-10-65296495; Fax: 01186-10-65296491; E-mail: hbzhang2006@gmail.com or hbzhang@ibms.pumc.edu.cn.

View this article at: http://www.jci.org/articles/view/37964?key=tW45bTOVxrubVqRN67Lq

TITLE: New roles for Notch in tuberous sclerosis

Warren S. Pear
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-7764; Fax: (215) 573-6875; E-mail: wpear@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/41897?key=4b97bbae87d939f277f7

EDITOR'S PICK: Common mechanism underlies many diseases of excitability

Inherited mutations in voltage-gated sodium channels (Navs) are associated with many different human diseases, including genetic forms of epilepsy and chronic pain. Theodore Cummins and colleagues, at Indiana University School of Medicine, Indianapolis, have now determined the functional consequence of three such mutations. As noted by Stephen Cannon and Bruce Bean, in an accompanying commentary, these results suggest that there might be a common mechanism for many channelopathies, diseases arising from mutations in ion channel genes such as those analyzed by Cummins and colleagues.

The authors studied the functional consequences of mutations in the human peripheral neuronal sodium channel Nav1.7, the human skeletal muscle sodium channel Nav1.4, and the human heart sodium channel Nav1.5, which are associated with an extreme pain disorder, a muscle condition characterized by slow relaxation of the muscles, and a heart condition and sudden infant death syndrome, respectively. Expression of these mutated proteins in a rat-derived dorsal root ganglion neuronal system led to the conclusion that the mutations all altered opening of the sodium channels such that the channels quickly reopened after an electrical impulse had been fired by the nerve cell causing a resurgent sodium current that triggered a second electrical impulse to be fired rapidly after the first. These observations are consistent with the diseases all being characterized by excitability, over activity of cells that rely on electrical currents, such as nerve cells, skeletal muscle cells, and heart muscle cells.

TITLE: Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

Theodore R. Cummins
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: (317) 278-9342; Fax: (317) 278-5849; E-mail: trcummin@iupui.edu.

View this article at: http://www.jci.org/articles/view/40801?key=5c50c65d9dc478d53b04

TITLE: Sodium channels gone wild: resurgent current from neuronal and muscle channelopathies

Stephen C. Cannon
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 645-6225; Fax: (214) 645-6239; E-mail: steve.cannon@utsouthwestern.edu.

View this article at: http://www.jci.org/articles/view/41340?key=Zo8jH8YTR4w86PqUFq0w

TUMOR IMMUNOLOGY: Human tumor-targeting immune cells inhibited by the protein BTLA

Immune cells known as CD8+ T cells have important roles in protection against infectious diseases and cancer. Now, Daniel Speiser and colleagues, at the Ludwig Institute for Cancer Research, Switzerland, have determined that human CD8+ T cells that target tumors express much higher levels of an inhibitory molecule known as BTLA than human CD8+ T cells that target viruses. Triggering of BTLA on these cells impaired their function. Further, persistently high levels of BTLA expression were detected on tumor-specific CD8+ T cells from melanoma patients who mounted spontaneous antitumor immune responses and after conventional peptide vaccination. More importantly, treating melanoma patients with both conventional peptide vaccination and a compound that decreased BTLA expression on tumor-specific CD8+ T cells restored the ex vivo functionality of the T cells. The authors and, in an accompanying commentary, Chrystal Paulos and Carl June therefore suggest that it might be useful to combine approaches to inhibit BTLA-mediated T cell inhibition with conventional cancer vaccination strategies.

TITLE: BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

Daniel E. Speiser
Ludwig Institute for Cancer Research, Hôpital Orthopédique, Lausanne, Switzerland. Phone: 41-21-314-01-82; Fax: 41-21-314-74-77. E-mail: daniel.speiser@hospvd.ch.

View this article at: http://www.jci.org/articles/view/40070?key=23PVktf8PwK4PDwx59te

TITLE: Putting the brakes on BTLA in T cell–mediated cancer immunotherapy

Chrystal M. Paulos
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (202) 557-1868; Fax: (215) 573-8590; E-mail: chrystal.paulos@gmail.com.

Carl June
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5745; Fax: (215) 573-8590; E-mail: cjune@exchange.upenn.edu.

View this article at: http://www.jci.org/articles/view/41811?key=956f709daabf4479246d

CARDIOLOGY: Why diseased heart muscle cells don't communicate properly

The heartbeat is controlled by rapid conduction of an electrical current between heart muscle cells. Central to passage of the electrical current are structures known as gap junctions, low resistance conduits that link heart muscle cells and consist of proteins known as connexins. Many forms of heart disease are associated with decreased gap junction coupling, and these changes predispose to abnormal heartbeats, which can be lethal. Robin Shaw and colleagues, at the University of California at San Francisco, have now identified a reason why there is decreased gap junction coupling in these situations using human, mouse, and zebrafish heart tissue.

In the study, the protein EB1, which delivers connexins to gap junctions, was found to be displaced in ischemic human hearts, stressed mouse hearts, and isolated cells subjected to oxidative stress, leading to decreased gap junction coupling. Further, in zebrafish hearts, oxidative stress reduced the membrane localization of connexin and slowed the spread of electrical currents. The authors hope that developing approaches to preserve the ability of cells to transport connexins to the cell surface to form gap junctions might reduce potentially lethal abnormal heartbeats in humans with diseased hearts.

In an accompanying commentary, Gordon Tomaselli, at Johns Hopkins University School of Medicine, Baltimore, discusses the importance of maintaining normal gap junction function in the heart and explains how the work of Shaw and colleagues fits into the complex puzzle that is our understanding of how heart muscle cells communicate.

TITLE: Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium

Robin M. Shaw
University of California at San Francisco, San Francisco, California, USA.
Phone: (415) 476-0626; Fax (415) 476-0424; E-mail: shawrm@medicine.ucsf.edu.

View this article at: http://www.jci.org/articles/view/39740?key=8c29498debaae6b0078a

TITLE: Oxidant stress derails the cardiac connexon connection

Gordon F. Tomaselli
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 955-2774; Fax: (410) 502-2096; E-mail: gtomasel@jhmi.edu.

View this article at: http://www.jci.org/articles/view/41780?key=cdb89ce1810bde668cd3

VASCULAR BIOLOGY: Starting out early: the role of the molecule RANTES in arterial blood vessel injury

Damage to the wall of arterial blood vessels leads to the formation of structures known as neointimal lesions. If these structures do not resolve, they cause narrowing of the blood vessel, which leads to oxygen deprivation in the tissues fed by the blood vessels and subsequent tissue and organ damage. Manfred Boehm and colleagues, at the National Institutes of Health, Bethesda, have now identified some of the early events that occur immediately after arterial blood vessel damage in the mouse, providing information about a stage of the response to arterial blood vessel injury not previously well understood.

In the study, when mouse arterial blood vessels were subject to damage, cells in the blood vessel wall known as vascular smooth muscle cells (VSMCs) upregulated expression of a protein known as RANTES. The RANTES was secreted by the VSMCs and attracted inflammatory cells known as T cells and macrophages to the region of arterial blood vessel damage. Detailed analysis revealed that VSCM expression of RANTES was triggered by the molecule TNF-alpha and was dependent on the gene regulatory molecules STAT3 and NF-kappa-B. Consistent with this, both mice lacking TNF-alpha and mice lacking STAT3 in VSMCs produced less RANTES after arterial blood vessel damage than did normal mice. The importance of these data are highlighted and put into the context of the bigger picture of arterial blood vessel damage in an accompanying commentary by Timothy Hla and Myat Lin Oo, at Weill Medical College of Cornell University, New York.

TITLE: STAT3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice

Manfred Boehm
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 435-7211; Fax: (301) 451-7090; E-mail: boehmm@nhlbi.nih.gov.

View this article at: http://www.jci.org/articles/view/40364?key=GhecNa63I2pYyDkbM7e2

TITLE: Ramping up RANTES in the acute response to arterial injury

Timothy Hla
Weill Medical College of Cornell University, New York, New York, USA.
Phone: (212) 746-9953; Fax: (212) 746-2830; E-mail: tih2002@med.cornell.edu.

View this article at: http://www.jci.org/articles/view/41738?key=ad222b92582f94268bff


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