ONCOLOGY: Cbx7 suppresses tumor growth

The unregulated cell growth that occurs in cancer is in part related to changes in the expression of genes that control the cell cycle. CBX7 is a gene known to be involved in a repressor complex that is capable of altering the proteins around which DNA is wrapped such that genes cannot be expressed. Previous research has implicated the loss of CBX7 in cancer progression; its loss is correlated with malignancy and poor prognosis in many tumor types. In new research, Alfredo Fusco and colleagues, of Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, in Naples, Italy, generated mice that lacked Cbx7 expression. Remarkably, these mutant mice spontaneously developed malignant growths in the liver and lung. The researchers also demonstrated that CBX7 acts in part by regulating expression of the cell cycle protein CyclinE. These results show that Cbx7 normally acts as a tumor suppressor, keeping cell growth in check.

TITLE: CBX7 is a tumor suppressor in mice and humans

View this article at: http://www.jci.org/articles/view/58620?key=91439f519d2c6db02b01

DERMATOLOGY: Zinc-deficient individuals irritated by ATP

Zinc (Zn) is an essential trace element. Zn deficiency can be inherited or acquired, for example as a result of low dietary Zn intake. It has many clinical manifestations, including secondary bacterial and fungal infection of skin lesions due to impaired immune function, however the mechanism through which Zn-deficient individuals develop skin inflammation is unknown. In this paper, Kawamura and colleagues, of the University of Yamanashi, in Japan, determined that mice fed a Zn-deficient diet (ZD mice) develop a severe irritant contact dermatitis (ICD) that has the histological features of the skin inflammation seen in Zn-deficient individuals. Detailed analysis revealed that irritant- injured keratinocytes released ATP causing ICD in this model. The ZD mice had decreased numbers of epidermal Langerhans cells (LCs), which are known to hydrolyze ATP and thereby provide protection against ATP-mediated inflammatory conditions such as ICD. The researchers found that Zn-deficient individuals also lacked epidermal LCs. Kawamura and colleagues suggest that ATP released from injured keratinocytes, which accumulates because there are insufficient epidermal LCs to hydrolyze it, causes the skin inflammation observed in Zn-deficiency.

TITLE: Severe dermatitis with loss of epidermal Langerhans cells in human and mouse zinc deficiency

View this article at: http://www.jci.org/articles/view/58618?key=eee11997df6e91290768

NEUROLOGICAL DISEASE: New insight into genetic movement disorder

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a genetic movement disorder, with episodes precipitated by alcohol, coffee, and stress. It is caused by mutations in the PNKD gene, but the normal function of that gene had been a mystery. In new research, Louis J. Ptáček and colleagues at the University of California, San Francisco, investigated the expression pattern and function of Pknd in mice. The group generated mice that expressed known human disease mutations in Pnkd, and found that mouse had a movement disorder similar to the human disease. In these mice, attacks of dyskinesia were characterized by activation of neurons in the basal ganglia and alteration of dopamine signaling in the striatum. This research helps uncover the function of PKND, and in part explains what goes wrong in PKND patients.

TITLE: Dopamine dysregulation in a mouse model of paroxysmal non-kinesigenic dyskinesia

View this article at: http://www.jci.org/articles/view/58470?key=4c19485504835cbbf900

ONCOLOGY: CHCHD4 helps cancer cells adapt to ch-ch-ch-ch- changes in oxygen availability

The ability of cells to respond to changes in oxygen level is a key determinant of their survival. In many cancer cells, for example, one component of the hypoxia inducible factor complex (HIF-1α) is chronically upregulated, which can result in increased blood vessel density and thus nutrient and oxygen delivery to growing tumors. In this paper, Margaret Ashcroft and her team, at University College, London, describe a mitochondrial protein called CHCHD4 that increases the rate at which cells consume and metabolize oxygen, and is critical for the induction of HIF-1α expression in response to low oxygen levels. They found that decreasing CHCHD4 expression inhibits the ability of cancer cells to form tumors. Furthermore, in cancer patients, increased CHCHD4 expression correlated with the hypoxia gene expression signature, increasing tumor grade, and reduced patient survival. This research identifies a mechanism that is critical for regulating the hypoxic response in tumors, and could indicate a new direction for those searching for strategies to fight tumor growth.

TITLE: Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression

View this article at: http://www.jci.org/articles/view/58780?key=f74fccbc0af7545e61d8

VASCULAR BIOLOGY: Link between hypercholesterolemia and blood clots can be broken by statins

High levels of cholesterol in the blood is very common, and can lead to hardening of arteries (atherosclerosis), the formation of plaques, and eventually the complete blockage of blood vessels. Hypercholesterolemia is also associated with a procoagulant state characterized by platelet hyperactivity. It has previously been shown that when LDL (the "bad cholesterol") is oxidized (forming oxLDL), it can induce an immune response and induce expression of the pro-coagulant protein tissue factor (TF) in monocytes/macrophages, endothelial cells, and smooth muscle cells. In new research, Nigel Mackman and colleagues, at the University of North Carolina at Chapel Hill, confirmed previous findings that high cholesterol results in a pro-coagulant state and activation of platelets in human patients. They then investigated the mechanism by which hypercholesterolemia leads to activation of coagulation. They found that genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice. Treatment of hypercholesterolemic mice and monkeys with the statin simvastatin, which inhibits TF expression in monocytes and macrophages, reduced oxLDL, monocyte TF expression, activation of coagulation, and inflammation without affecting total cholesterol levels. These results suggest that the pro-thrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of monocyte TF expression.

In the accompanying commentary, Roy Silverstein, of the Medical College of Wisconsin, explains these findings also provide a new understanding of statin action, and suggests that targeting this pathway could be useful in the treatment of thrombosis.

TITLE: Monocyte tissue factor - dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

View this article at: http://www.jci.org/articles/view/58969?key=b8d507e8dd483209c4ad

ACCOMPANYING COMMENTARY TITLE: Teaching an old dog new tricks: potential antiatherothrombotic use for statins

View this article at: http://www.jci.org/articles/view/61857?key=38138bc567017dc85bec

ONCOLOGY: Cooperation between two mutations drives ovarian cancer

Erroneous activation of signaling pathways that drive cell growth occurs in many human cancers. Mutations in one subunit of PI3K (encoded by PIK3CA) are frequent in human tumors, and these can lead to activation of the AKT signaling pathway. However, it was unclear whether this mutation was sufficient to drive tumor development. In this paper, Wayne Philips and his team, at the Peter MacCallum Cancer Center in Melbourne, Australia, generated a conditional knock-in mouse model of a common human Pik3ca mutation. They found that on its own, expression of this mutation in the mouse ovary induced premalignant hyperplasia of the ovarian surface epithelium (OSE), but not tumors. However, when the Pik3ca mutation was expressed in combination with deletion of the tumor suppressor Pten, mice developed ovarian serous adenocarcinomas and granulosa cell tumors. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. The researchers believe that this work shows that these two mutations are sufficient to drive tumor development, and hope that their model system will be useful for the testing of new therapeutics.

TITLE: An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

View this article at: http://www.jci.org/articles/view/59309?key=6304f99669c209a9087e

INFECTIOUS DISEASE: New technique to identify viral vaccine targets

Herpes simplex virus type 1 (HSV-1) is a common human virus that causes cold sores, can lead to brain damage and blindness, and causes some genital herpes. An effective vaccine for HSV-1 will need to stimulate responses from multiple types of immune cells, including both helper and memory T cells. To do so, scientists must first identify the antigens from the virus capable of stimulating T cells. In new research, David Koelle and colleagues, at the University of Washington, Seattle, developed a system to stimulate memory and helper T cells from HSV-1 positive patients, and then isolate those that were specifically reactive to HSV-1. This technique led to the identification of previously unidentified HSV-1 vaccine candidate genes. The researchers then successfully applied their technique to identify T cell antigens of the vaccinia virus, suggesting that it may be useful for the identification of T cell vaccine targets for many other viruses.

TITLE: Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

View this article at: http://www.jci.org/articles/view/60556?key=1090dd956228d894d025