EDITOR'S PICK: New suppressor of common liver cancer
Tumor suppressor genes make proteins that help control cell growth. Mutations in these genes that generate nonfunctional proteins can contribute to tumor development and progression. One of the most well-known tumor suppressor genes is BRACA1, mutations in which are linked to breast cancer. Ze-Guang Han and colleagues, at the Chinese National Human Genome Center at Shanghai, People's Republic of China, have now identified SCARA5 as a candidate tumor suppressor gene in human hepatocellular carcinoma (HCC), a form of liver cancer that is the fifth most common cancer worldwide.
While it has been known for a long time that genetic inactivation of tumor suppressor genes can contribute to tumor development and progression, only more recently has it been determined that inactivating tumor suppressor genes by a mechanism known as epigenetic silencing has the same effect. In the study, analysis of HCC tissue samples indicted that SCARA5 was frequently subjected to genetic loss and epigenetic silencing and that SCARA5 protein downregulation was most marked in HCC tissue samples characterized by tumor invasion into the blood vessels (a sign of aggressive disease). Further analysis in HCC cells lines in vitro and after xenotransplantation into mice were consistent with SCARA5 being a tumor suppressor gene. The authors therefore suggest that SCARA5 protein downregulation as a result of SCARA5 genetic loss and epigenetic silencing can contribute to HCC tumor development and progression.
TITLE: Genetic and epigenetic silencing of SCARA5 may contribute to human hepatocellular carcinoma by activating FAK signaling
Chinese National Human Genome Center at Shanghai, Shanghai, People's Republic of China.
Phone: 86-21-50801325; Fax: 86-21-50800402; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/38012?key=WYUeOaDgqG3U70r15PKV
EDITOR'S PICK: Genetic link to heart failure
A team of researchers, at Washington University School of Medicine, St Louis, has identified a group of 12 genetic variants in the HSPB7 gene that is associated with heart failure in humans.
The team, led by Gerald Dorn, used an approach they have recently developed that allows ultra-high-throughput targeted DNA sequencing to identify genetic variation in four genes with biological relevance to heart failure. They identified in a large group of Caucasian individuals with heart failure, 129 separate genetic variants in the four genes, including 23 that seemed to be novel. Further analysis of 1117 Caucasian individuals with heart failure and 625 nonaffected Caucasians indicated that a block of 12 genetic variants in the HSPB7 gene was associated with heart failure. Confirmation of this association was provided by analysis of an independent group of individuals. The authors hope to use the same approach to identify further genetic variants associated with heart failure, a disease that is influenced by multiple genetic factors.
TITLE: Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease
Gerald W. Dorn, II
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-4892; Fax: (314) 362-8844; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/39085?key=QR23mwtIf19sIud3dWA9
VASCULAR BIOLOGY: Signaling decreased blood pressure
Blood pressure is controlled in part by changes in the radius of blood vessels; when the smooth muscle cells in the wall of a blood vessel contract, the radius of the blood vessel decreases and blood pressure increases. A team of researchers at CSIC–University of Salamanca, Spain, has now identified in mice a new signaling pathway that contributes to relaxation of smooth muscle cells in blood vessel walls triggered by the molecule NO and thereby decreases blood pressure.
Mice lacking the protein Vav2 have elevated blood pressure. By analyzing these mice, the team, led by Xosé Bustelo, identified a Vav2 signaling pathway that normally contributes to NO-triggered relaxation of smooth muscle cells in blood vessel walls. The pathway involves Vav2 activation of the proteins Rac1 and Pak1. Absence of Pak1 activation in Vav2-deficient mice resulted in excessive activity of the protein phosphodiesterase type 5. Consistent with this, treating Vav2-deficient mice with phosphodiesterase type 5 inhibitors reduced their blood pressure to a normal level. As defective blood vessel reactivity to NO contributes to the symptoms of diseases such as atherosclerosis (hardening of the arteries) and diabetes, the authors suggest that stimulating the pathway they have identified might be of therapeutic benefit in patients with these diseases.
TITLE: The Rho/Rac exchange factor Vav2 controls nitric oxide–dependent responses in mouse vascular smooth muscle cells
Xosé R. Bustelo
CSIC–University of Salamanca, Campus Unamuno, Salamanca, Spain.
Phone: 34-923294802; Fax: 34-923294743; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/38356?key=VFkTwWePlatxwBXqdW3x
ONCOLOGY: How cancer cells protect themselves from low levels of oxygen
Not all regions of a tumor are equal in terms of their oxygen levels. One clinically important implication of this is that tumors with large areas with low levels of oxygen (areas known as hypoxic regions) are associated with poor prognosis and treatment response. A team of researchers, led by Bradly Wouters, at the University of Toronto, Canada, has determined that a cellular response pathway known as the unfolded protein response pathway helps protect human tumor cells from hypoxia and anticancer irradiation treatment. Further analysis indicated that the unfolded response pathway increased expression of two proteins involved in a cellular process known as autophagy, which is known to act to protect cells in times of stress. Importantly, inhibition of autophagy sensitized cultured human tumor cells to hypoxia and sensitized human tumors xenografted into mice to irradiation, leading the authors to suggest that targeting the molecules they identified as important might be of clinical benefit.
TITLE: The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5
Bradly G. Wouters
University of Toronto, Toronto, Ontario, Canada.
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View this article at: http://www.jci.org/articles/view/40027?key=R0gn8cJB89Pz98D0OF8t
METABOLISM: Bone control of glucose levels
Bone cells known as osteoblasts were recently shown to have a role in controlling the biochemical reactions that generate energy via secretion of the molecule osteocalcin. A team of researchers, led by Stavroula Kousteni, at Columbia University, New York, has now determined that the protein FoxO1 regulates this function of osteoblasts in mice. Specifically, FoxO1 increases expression of osteocalcin and decreases expression of Esp, a gene that makes a protein responsible for decreasing the bioactivity of osteocalcin. This is a new role for FoxO1, which is also involved in regulating glucose levels via effects on cells in the pancreas and liver.
TITLE: FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice
Columbia University, New York, New York, USA.
Phone: (212) 851-5223; Fax: (212) 851-5225; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/39901?key=IsEkHw3z3h7LJTXqmYDH
NEPHROLOGY: Soluble immune molecules cause acute kidney inflammation in mice
Immune molecules known as cytokines are effectors of immune cell function. The IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways have been linked to autoimmune diseases (i.e, diseases in which the immune system turns on the body). A team of researchers, led by Li Li, at the University of Virginia, Charlottesville, has now determined that these cytokine pathways also contribute to inflammation in a mouse model of acute kidney injury. Specifically, they find that the IL-23/IL-17 pathway works upstream of the IL-12/IFN-gamma pathway, as IL-17A production by immune cells known as neutrophils was required for activation of the IL-12/IFN-gamma pathway. In addition, as the inflammation underlying kidney injury in this model was caused by blood flow returning to the kidney following a period in which the kidney was deprived of blood flow (an event known as reperfusion) and reperfusion injury has a role in brain and heart damage caused by stroke and heart attack, respectively, the authors suggest that the IL-23/IL-17 and IL-12/IFN-gamma cytokine pathways might contribute to reperfusion injury in other organs.
TITLE: IL-17 produced by neutrophils regulates IFN-gamma–mediated neutrophil migration in mouse kidney ischemia-reperfusion injury
University of Virginia, Charlottesville, Virginia, USA.
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View this article at: http://www.jci.org/articles/view/38702?key=Nwa5Q206lzzoF7Ydyxl4
Journal of Clinical Investigation