JCI table of contents: Oct. 12, 2006

October 12, 2006

EDITOR'S PICK

Waste not, want not: Role for caveolin-3 in muscular dystrophy

The muscular dystrophies are a group of genetic and hereditary diseases in which patients experience skeletal muscle weakness due to wasting and loss of muscle fibers. However, the signaling pathways involved in muscle wasting have remained elusive. Researchers have begun to focus on the potential role of proteins known as caveolins in muscle wasting. Caveolins come together to form a scaffold onto which many other types of signaling molecules can assemble at the cell plasma membrane. Caveolin-3 is a muscle-specific form of caveolins.

In a study appearing online on October 12, in advance of publication in the November print issue of the Journal of Clinical Investigation, Yoshihide Sunada and colleagues from Kawasaki Medical School, Japan, show that loss of caveolin-3 in a mouse model of muscular dystrophy increases the intracellular activity of myostatin - a known inhibitor of muscle growth - and leads to muscle wasting. Conversely, the authors demonstrated that inhibition of myostatin rescued the muscle wasting in these mice. The study indicates that overactivation of myostatin signaling plays an important role in the pathogenesis of muscular dystrophy in mice, and that a principal function of caveolin-3 in skeletal muscle is to inhibit myostatin signaling, thereby preventing muscle wasting. Future studies may show that myostatin inhibition may have potential as a promising therapy for patients with certain kinds of muscular dystrophy.

TITLE: Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition

AUTHOR CONTACT:

Yoshihide Sunada
Kawasaki Medical School, Kurashiki, Japan.
Phone: 81-86-462-1111; Fax: 81-86-462-1199; E-mail: ysunada@med.kawasaki-m.ac.jp.


View the PDF of this article at: https://www.the-jci.org/article.php?id=28520


ONCOLOGY

Elevated PTTG1 levels trigger mitotic mischief, causing thyroid cancer

During the cell division process known as mitosis the transmission of chromosomes from a parent cell to its daughter cells is a fundamental method by which genes are inherited. During the third phase (known as anaphase) of this four-phase process the daughter chromosomes separate. The pituitary tumor-transforming gene 1 (PTTG1) protein is critical to mitosis because it helps hold the daughter chromosomes together before entering anaphase. Overexpression of PTTG1 is associated with human thyroid cancer, however the events that trigger PTTG1 accumulation are not well understood.

In a study appearing online on October 12, in advance of publication in the November print issue of the Journal of Clinical Investigation, Sheue-yann Cheng and colleagues from the National Cancer Institute show that, normally, PTTG1 is degraded via its physical association with thyroid hormone beta receptor (TRbeta), which binds thyroid hormone (T3). This degradation allows chromosome separation to proceed during anaphase. However, in a mouse model of thyroid cancer a mutant form of TRbeta, which is unable to bind T3, failed to trigger PTTG1 degradation, resulting in elevated PTTG1 protein levels. This caused abnormalities in the mitotic process such that daughter cells received one or more chromosomes above or below the normal chromosome number (a condition known as aneuploidy), which the authors suggest could contribute to the development of thyroid carcinoma.

TITLE: Aberrant accumulation of PTTG1 induced by a mutated thyroid hormone beta receptor inhibits mitotic progression

AUTHOR CONTACT:

Sheue-yann Cheng
National Cancer Institute, Bethesda, Maryland, USA.
Phone: (301) 496-4280; Fax: (301) 402-1344; E-mail: chengs@mail.nih.gov.


View the PDF of this article at: https://www.the-jci.org/article.php?id=28598


IMMUNOLOGY

NF-kappaB2 teaches tolerance

The immune system is designed to recognize millions of different proteins so that infectious agents do not slip through its defenses. However, this means that some components of the immune system recognize proteins that belong to the body's own tissues. During evolution, several ways to teach the immune system to tolerate the body's own tissues have developed. For example, as T cells develop in the thymus, those cells that easily recognize proteins that belong to the body's own tissues [the expression of which are controlled by a protein known as autoimmune regulator (AIRE)] are eliminated. If this process breaks down, such as in individuals with defects in the AIRE gene, T cells attack the body's own tissues causing autoimmunity. Given the importance of the gene, understanding how AIRE is regulated is an area of intensive research.

In a study appearing online on October 12 in advance of publication in the November print issue of the Journal of Clinical Investigation, Yang-Xin Fu and colleagues from Chicago University have shown that in mice, NF-kappaB2 is required for Aire gene expression in the thymus. Mice lacking NF-kappaB2 had a similar autoimmune phenotype to mice lacking Aire, and Aire expression was dramatically reduced in the thymus of NF-kappaB2-deficient mice. This study identifies one pathway by which the expression of proteins that belong to the body's own tissues is controlled in the thymus, providing insight into the mechanisms that have evolved to ensure that the immune system tolerates the body's own tissues.

TITLE: NF-kappaB2 is required for the establishment of central tolerance through and Aire-dependent pathway

AUTHOR CONTACT:

Yang-Xin Fu
University of Chicago, Chicago, Illinois, USA.
Phone : (773) 702-0929 Fax: (773) 834-8940; E-mail: yfu@uchicago.edu.


View the PDF of this article at: https://www.the-jci.org/article.php?id=28326


IMMUNOLOGY

Type I IFNs beat IFN-gamma to the immunoproteasome

CD8+ T cells are immune cells that have a central role in clearing viral infections. Virus-specific CD8+ T cells become activated when they recognize small fragments of viral proteins, which are generated by a protein complex known as the proteasome, bound to a protein known as MHC class I on the surface of a virus-infected cell. Although the pro-inflammatory soluble factor IFN-gamma is known to alter the composition and function of the proteasome, generating the immunoproteasome, it is not known whether related soluble factors (type I INFs) released before IFN-gamma during viral infection can also generate the immunoproteasome.

Now, in a study appearing online on October 12 in advance of publication in the November print issue of the Journal of Clinical Investigation, Barbara Rehermann and colleagues from the National Institutes of Health, have shown that type I IFNs generate the immunoproteasome in human liver cells. More importantly, hepatitis C virus (HCV) RNA generated the immunoproteasome in a type I IFN-dependent manner and the immunoproteasome was expressed in the liver of chimpanzees infected with HCV with the same kinetics as type I IFN expression and before the induction of IFN-gamma. The authors therefore suggest that treatment with type I IFNs, a highly effective therapy for acute infection with hepatitis C virus, might sustain immunoproteasome expression and increase the chance that virus-infected cells are recognized by CD8+ T cells.

TITLE: Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection

AUTHOR CONTACT:

Barbara Rehermann
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.
Phone: (301) 402-7144; Fax: (301) 402-0491; E-mail: Rehermann@nih.gov.


View the PDF of this article at: https://www.the-jci.org/article.php?id=29832
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