JCI table of contents: August 10, 2006


Protein plays broader role than originally thought in neurofibromatosis

Neurofibromatosis type I is a common genetic disorder in which tumors grow along certain types of nerves and can also affect other tissues such as bone, heart, and skin. The condition is caused by a mutation in the gene coding for Neurofibromin (NF1), a GTPase-activating protein (GAP) that triggers the abnormal activation of the protein Ras, and clinical trials are currently underway using agents that downregulate Ras activity. However, it remains unclear whether modulation of Ras activity is the only, or even major function of neurofibromin.

In a study appearing online on August 10 in advance of print publication in the September issue of the Journal of Clinical Investigation, Fraz Ismat and colleagues from The Children's Hospital of Philadelphia examined a mouse model of Neurofibromatosis type I disease and showed that restoration of Ras-GAP activity through expression of the human NF1 GAP-related domain was able to restore normal cardiac development in these animals. However, not all pathologies associated with the loss of the neurofibromin protein were restored in these mice, indicating that neurofibromin is an important molecule in events beyond just Ras signaling. These results suggest that therapeutic approaches solely aimed at targeting Ras activity may not be sufficient to treat all tumors in patients with this disease.

TITLE: The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1-/- mice

Fraz A. Ismat
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: (267) 426-7937; Fax: (215) 590-5825; E-mail: ismat@email.chop.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=28341


Interferon-gamma keeps over-aggressive immune responses in check

Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress overactivation of the immune system and prevent it from turning upon self-tissues.

Initially, the expression of two cell surface molecules (CD4 and CD25) was used to define the Treg population of cells; as such they are often referred to as CD4+CD25+ Tregs. More recently the transcription factor Foxp3 has been identified to be exclusively expressed by Tregs and is known to play a key role in the conversion of CD4+CD25- T cells to CD4+CD25+ Tregs.

In a study in mice appearing online on August 10 in advance of print publication in the September issue of the Journal of Clinical Investigation, Jingwu Zhang and colleagues from the Shanghai Institute of Immunology have shown that interferon-gamma is required for the induction of Foxp3, resulting in the conversion of CD4+CD25- T cells to CD4+CD25+ Tregs. These results reflect the critical role that interferon-gamma plays in maintaining a balanced immune response: in the event of overt inflammation as a result of injury or infection, interferon-gamma acts as part of a self-regulatory mechanism to help keep the immune response in check by triggering the development of Tregs. This mechanism likely plays a role in other pathological conditions involving inflammation.

TITLE: Role of IFN-gamma in induction of Foxp3 and conversion of CD4+CD25- T cells to CD4+ Tregs

Jingwu Zhang
Shanghai Institute of Immunology, Shanghai, People's Republic of China.
Phone: 86-21-63848329; Fax: 86-21-63852822; E-mail: jzang@bcm.tmc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25826


Antibody binding to heart muscle cells disrupts the beating heart

Congenital heart block (CHB) is a condition in which the transfer of electrical nerve impulses that regulate the rhythmic pumping of heart muscle is altered. Although CHB is strongly associated with the transfer, via the placenta, from mother to fetus of antibodies to the ribonucleoproteins SSA/Ro and/or SSB/La, the precise role of these antibodies in CHB was not previously known. Healthy cardiac myocytes are involved in the normal removal of other apoptotic cardiac myocytes that have reached the end of their life cycle.

Now, in a study in both mice and humans appearing online on August 10 in advance of print publication in the September issue of the Journal of Clinical Investigation, Robert Clancy and colleagues from New York University School of Medicine show that the binding of anti-SSA/Ro and/or SSB/La antibodies inhibits this clearance process. This results in the accumulation of apoptotic cells, which promotes inflammation and subsequent scarring of the heart muscle, thereby disrupting the transfer of electrical nerve impulses and causing CHB.

TITLE: Impaired clearance of apoptotic cardiocytes is linked to anti-SSA/Ro and –SSB/La antibodies in the pathogenesis of congenital heart block

Robert M. Clancy
New York University School of Medicine, New York, New York, USA.
Phone : (212) 263-0745; Fax: (212) 263-0759; E-mail: bobdclancy@aol.com

View the PDF of this article at: https://www.the-jci.org/article.php?id=27803


The factor has two faces: dual role for FoxO1 in metabolic disease

Insulin controls in part how we metabolize both carbohydrates (glucose) and fats through distinct signaling pathways, however researchers have yet to identify if there is a shared element in these signaling pathways. In a study in mice appearing online on August 10 in advance of print publication in the September issue of the Journal of Clinical Investigation, Domenico Accili and colleagues from Columbia University show that a dual role exists for the transcription factor FoxO1 as the shared element in insulin signaling that controls both fat and glucose metabolism. They show that FoxO1 can have seemingly opposite effects on metabolism, with the ultimate goal of fine-tuning insulin sensitivity. FoxO1 increases insulin sensitivity by promoting Akt phosphorylation, and this step is associated with the repression of the enzyme Trb3, a modulator of Akt activity. This unexpected dual role of Foxo1 in promoting insulin sensitivity and fat synthesis in addition to glucose production has the potential to explain the mix of insulin resistance and sensitivity that is commonly observed in individuals with the metabolic syndrome. The study also suggests that Trb3 is an exciting new target of insulin action and therefore understanding how Trb3 is regulated has many ramifications for insulin resistance and diabetes.

TITLE: Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism

Domenico Accili
Columbia University Medical Center, New York, New York, USA.
Phone: (212) 851-5332; Fax: (212) 851-5331; E-mail: da230@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=27047


Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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