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JCI online early table of contents: March 9, 2009

EDITOR'S PICK: SOX9 renders melanomas sensitive to retinoic acid and stops tumor growth

Melanomas are often resistant to standard cancer therapies such as radiotherapy, chemotherapy, and retinoic acid (RA). Given the lack of available treatments for melanoma, the prognosis for patients is often poor. However, Vincent Hearing and colleagues at the National Cancer Institute at the National Institutes of Health in Bethesda, Maryland, have now found a way to restore the sensitivity of melanomas to RA, suggesting that this noncytotoxic therapeutic approach may be a viable option for melanoma treatment. Overexpression of SOX9, a transcription factor, not only restored RA sensitivity of mouse and human melanomas, but remarkably stopped tumor growth. The authors suggest that a combined therapeutic strategy, increasing the expression of SOX9 while simultaneously treating with RA, may provide new hope to effectively treat RA-resistant cancers such as melanoma.

TITLE: Upregulation of SOX9 inhibits the growth of human and mouse melanoma and restores their sensitivity to retinoic acid

Vincent J. Hearing
National Cancer Institute, Bethesda, Maryland, USA.
Phone: (301) 496-1564; Fax: (301) 402-8787; E-mail:

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PHYSIOLOGY: Two enzymes are crucial for ureter-bladder connection during development

Congenital anomalies that affect how the ureter is positioned within the bladder wall are frequent in newborns and can cause severe kidney dysfunction. However, little is known about the developmental processes responsible for ureter-bladder connection. In their new study, Maxime Bouchard and colleagues at McGill University in Montreal have studied the development of the urogenital system in mice and identified two receptor protein tyrosine phosphatases (RPTPs), types S and F (Ptprs and Ptprf, respectively) as being crucially important for both distal ureter maturation and craniofacial morphogenesis. Embryos lacking the genes that code for Ptprs and Ptprf displayed severe urogenital malformations and craniofacial defects such as cleft palate. The data suggest that these two RPTPs normally act redundantly to control key apoptotic events in the distal common nephric duct, allowing correct positioning of the developing ureter against the forming bladder, and subsequent apoptosis in the distal ureter that then allows proper connection of the ureter to the bladder wall. In the absence of these apoptotic events, the ureter fails to contact the bladder, resulting in ureter-bladder malformation. Based on these data, Bouchard et al. present an updated model of how maturation of the ureter-bladder connection takes place.

TITLE: Maturation of ureter-bladder connection in mice is controlled by LAR-family receptor protein tyrosine phosphatases

Maxime Bouchard
McGill University, Montreal, Quebec, Canada.
Phone: (514) 398-3532; Fax: (514) 398-6769; E-mail:

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CARDIOLOGY: The enzyme CaMKII modulates cardiac inflammation after a heart attack

Inhibition of the enzyme CaMKII (calcium/calmodulin-dependent protein kinase II) has been shown to improve cardiac function after a heart attack, but the CaMKII-dependent signaling pathways involved in the heart's response to stress are not well understood. In their new study, Madhu Singh, Mark Anderson, and colleagues at the University of Iowa, investigate the effects of CaMKII inhibition in the mouse heart after a heart attack. They found that CaMKII inhibition substantially reduced the expression of inflammatory proteins that are usually upregulated following a heart attack. They report that the expression of one such protein, complement factor B (CFB), is triggered by CaMKII activation during heart attack or exposure to a bacterial endotoxin, and that mice lacking the Cfb gene were partially protected from the adverse consequences of a heart attack. The data suggest that CaMKII is important in regulating inflammatory gene expression following a heart attack.

TITLE: Ca2+/calmodulin-dependent kinase II triggers cell membrane injury by inducing complement factor B gene expression in the mouse heart

Madhu V. Singh
Carver College of Medicine, University of Iowa, Iowa, City, Iowa, USA.
Phone: (319) 335-8954; Fax: (319) 353-5552; E-mail:

Mark E. Anderson
Carver College of Medicine, University of Iowa, Iowa, City, Iowa, USA.
Phone: (319) 353-7101; Fax: (319) 353-6343; E-mail:

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STEM CELLS: The protein MuPAR regulates the proliferation and mobilization of blood stem cells

The mechanisms underlying the adhesion and mobilization of hematopoietic stem/progenitor cells (HSPCs), cells that give rise to all other blood cell types, have been poorly understood. Using wild-type and genetically manipulated mice, Peter Carmeliet and his colleagues at Katholieke Universiteit Leuvan, Belgium, reveal in a new study that a membrane-anchored form of the urokinase receptor known as MuPAR is present on a subset of HSPCs and helps maintain this cell population in the bone marrow.

When MuPAR was deleted or inhibited, HSPC proliferation was increased, but the ability of these cells to home and adhere to the bone marrow microenvironment was inhibited. Furthermore, the authors show that MuPAR is inactivated by plasmin, which triggers HSPC mobilization. Finally, loss of the gene encoding MuPAR impaired the ability of the HSPCs to repopulate the bone marrow in recipient mice. The authors conclude from these results that MuPAR and plasmin play key roles in regulating HSPC maintenance, homing, engraftment, and mobilization in the bone marrow.

TITLE: Membrane-anchored uPAR regulates the proliferation, marrow pool size, engraftment, and mobilization of mouse hematopoietic stem/progenitor cells

Peter Carmeliet
Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
Phone: 32-16-34-57-72; Fax: 32-16-34-59-90; E-mail:

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CARDIOVASCULAR DISEASE: Insulin resistance in liver cells reduces atherosclerosis

Individuals with type 2 diabetes have an increased risk of developing a disease known as atherosclerosis (or hardening of the arteries), which is a leading cause of heart attack and stroke. One characteristic of type 2 diabetes, altered levels of certain fats in the blood (a condition known as dyslipidemia), is thought to be a fundamental reason for the increased risk of developing atherosclerosis. However, the contribution to atherosclerosis risk of another characteristic of type 2 diabetes, the inability of cells to respond to the hormone insulin (a condition known as insulin resistance), has not been definitively determined. Seongah Han and colleagues at Columbia University, New York, have now found, surprisingly, that mice lacking the protein LDLR and expressing low levels of the receptor for insulin only in the liver developed less severe atherosclerosis than mice lacking LDLR, when fed a Western diet. This is probably because these mice also had reduced levels of the fat transporting molecules VLDL and LDL in the blood. The results of further analysis using additional mouse strains were consistent with the idea that liver cell insulin resistance does not contribute to the development of atherosclerosis in mice, and actually decreases the secretion of VLDL.

TITLE: Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice

Seongah Han
Department of Medicine, Columbia University, New York, New York, USA.
Phone: (212) 305-4899; Fax: (212) 305-5052; E-mail:

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Contact: Brooke Grindlinger
Journal of Clinical Investigation

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