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JCI early table of contents for July 9, 2012

Breathing easy: keeping airways open

Asthma is an increasingly common chronic disorder characterized by wheezing and shortness of breath. Symptoms are caused by excessive airway smooth muscle contraction; however mechanisms serving to keep airways open are not fully understood. Dean Sheppard and colleagues at the University of California at San Francisco have revealed a pathway required for preventing exaggerated airway smooth muscle contraction. Their work investigates a protein called α9β1, which is highly expressed in airway smooth muscle, and makes use of a mouse model that lacks α9β1 in smooth muscle. These mice exhibited increased airway narrowing, suggesting that α9β1 inhibits smooth muscle contraction. The enzyme SSAT, which breaks down polyamines such as spermine and spermidine, is known to bind α9β1 and is required for α9β1-mediated cell movement. Their results show that SSAT is also involved in restraining airway smooth muscle contraction, likely downstream of α9β1. Their work provides insight into a pathway counteracting airway contraction, which could be used to develop treatment options that prevent asthma symptoms.

Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Dean Sheppard
UCSF, San Francisco, CA, USA
Phone: 415-514-4269; Fax: 415-514-4278; E-mail:

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Crosstalk between glucose and lipid metabolism

Regulating metabolism requires coordination of the production, storage, and breakdown of nutrients in response to both availability and demand. Such regulation requires complex pathways to control the activity of metabolic enzymes and the rate at which metabolic genes are transcribed. Dr. Kristina Schoonjans and co-workers at the Ecole Polytechnique Fdrale in Lausanne, Switzerland report on the role of liver receptor homolog 1 (LRH-1), a transcription factor with important functions in lipid metabolism and reverse cholesterol transport. Their work uncovers new functions for LRH-1 in sensing and responding to glucose. In mice with conditional deletion of Lrh1 in liver, they observed impaired glucose production, reductions in the storage of glucose as liver glycogen, and less lipid generation in response to glucose exposure. Their work demonstrates that LRH-1 is important for glucose-sensing and for coordinating glucose and lipid metabolism after feeding.

LRH-1dependent glucose sensing determines intermediary metabolism in liver

Kristina Schoonjans
Ecole Polytechnique Fdrale de Lausanne, Lausanne, CHE
Phone: +41216931891; E-mail:

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Decreasing cancer risk associated with inflammatory bowel disease

Inflammatory bowel disease is caused by chronic inflammation , which leads to damage of the intestinal epithelium. Patients with inflammatory bowel disease have an elevated risk for developing colorectal cancer because of this chronic inflammation. In an effort to develop strategies to break the cycle of inflammation, Dr. Brent Polk and colleagues at the University of Southern California in Los Angeles examined two mouse models of colorectal cancer. Their work shows that inactivating a key receptor, known as epidermal growth factor receptor, increases the frequency and severity of colorectal tumors. Though epidermal growth factor has well-defined roles in promoting tumor growth, the Polk team now finds that epidermal growth factor receptor can ameliorate the response to chronic inflammation and reduces tumor development by fine-tuning inflammation and the generation of intestinal epithelium. Their results suggest that promoting epidermal growth factor activity in patients with inflammatory bowel disease could decrease long-term cancer risk by reducing inflammation.

Epidermal growth factor receptor inhibits colitis-associated cancer in mice

D. Brent Polk
University of Southern California and Childrens Hospital Los Angeles, Los Angeles, CA, USA
Phone: 323-361-2278; E-mail:

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Differentiating effects on skin cancer

Squamous cell carcinomas (SCCs), which are the most aggressive form of non-melanoma skin cancer, typically have functional impairment in the tumor suppressor protein p53. Dr. Erwin F. Wagner and colleagues from the Centro Nacional de Investigaciones Oncologicas in Madrid, Spain recently uncovered new mechanisms mediating p53 impairment and its role in SCC tumor suppression. They found that deletion of the Fos gene reduced tumor development in a mouse model of skin carcinogenesis. The FOS protein was found to directly repress p53, preventing its tumor suppression function. Deleting Fos and the gene encoding p53 together resulted in tumors with impaired differentiation. The Wagner team went onto show that p53 directly upregulates TACE, a metalloprotease, involved in cell differentiation. Levels of FOS in human tumor tissue correlated with inactive TACE expression and poorly differentiated tumors. Lastly, the combination of FOS inhibition and the presence of a normal gene encoding p53 caused differentiation and inhibited proliferation in cells derived from human SCCs. These results suggest inhibition of FOS and activation of the p53-TACE axis could be considered as future treatments for SCC.

Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17

Erwin F. Wagner
CNIO, Madrid, UNK, ESP

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Contact: Sarah Jackson
Journal of Clinical Investigation

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