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News From The Journal Of Clinical Investigation: July 9, 2012

Breathing easy: keeping open

Asthma is an increasingly common chronic disorder characterized by wheezing and shortness of breath. Symptoms are caused by excessive airway ; however mechanisms serving to keep airways open are not fully understood. and colleagues at have revealed a pathway required for preventing exaggerated airway . 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 . 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 , 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.

TITLE: Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing


METABOLISM 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 Fédérale in Lausanne, 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.

TITLE: LRH-1-dependent glucose sensing determines intermediary metabolism in liver


ONCOLOGY 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 . 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.

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



Journal of Clinical Investigation