July 10, 2009

Aliquots — research highlights from VUMC laboratories

An EGF receptor turn-on

The epidermal growth factor receptor (EGFR) – a target for cancer therapeutics in clinical use – is an important model for understanding the activation of tyrosine kinase receptors. Mutations that enhance tyrosine kinase activity of the EGFR (and related growth factor receptors) are associated with human cancers.

Graham Carpenter, Ph.D., and colleagues used mutagenesis and structural biology approaches to explore the role of the intracellular juxtamembrane (JM) region of the EGFR. They defined a JM activation domain that is required for kinase activity – in contrast to the inhibitory role of this region in other growth factor receptors. They also evaluated the impact of reported lung cancer mutations in this region on EGFR activity and demonstrated that a particular mutation activates the EGFR and promotes tumor-like cell growth in vitro and in vivo.

The findings in the June 26 issue of Molecular Cell suggest that the JM activation domain is important in regulating EGFR kinase activity and that mutations within this region may be oncogenic.

Leigh MacMillan


Oxygen sensor fine-tunes liver fat

Oxygen is an important signal that modulates metabolic activities and disease in the liver. Low oxygen conditions (hypoxia) – because of heart failure, obstructive sleep apnea or excessive alcohol use – are associated with fatty liver disease, but the regulation of fat metabolism under hypoxic conditions is not well understood.

Volker Haase, M.D., and colleagues investigated the function of hypoxia-inducible factors (HIF-1 and HIF-2), important components of the cellular oxygen-signaling pathway, in liver lipid metabolism. They inactivated HIF-1 or HIF-2 in the livers of mice that accumulate lipids in their livers and found that HIF-2, but not HIF-1, plays a major role in the development of fatty liver disease by inhibiting lipid oxidation and increasing fat storage.

The findings, reported in Molecular and Cellular Biology, demonstrate that HIF-2 functions as an important regulator of lipid metabolism in the liver and identify HIF-2 as a potential target for the treatment of fatty liver disease.

Leigh MacMillan


Sights, sounds offer mice a ‘thrill’

Thrill-seeking behavior in humans is often associated with drug abuse and addiction. Operant conditioning, in which an animal must perform a task (e.g., press a lever) to get a reward (e.g., food or drug), is commonly used to model drug addiction. But it is not clear what non-drug, non-food stimulus might be a useful correlate of “thrill seeking” in animals.
Christopher Olsen, Ph.D., and Danny Winder, Ph.D., evaluated mice for their ability to acquire an operant response (lever press) to a complex visual/auditory stimulus (a combination of flashing lights and a sound).

In the June issue of Neuropsychopharmacology, they report that mice readily acquired operant responding for this stimulus, similar to responses seen with drug and food reinforcers. They found that the response, dubbed “operant sensation seeking” (OSS), is sensitive to brain dopamine signaling, an effect also reported for drug self-administration. The findings suggest that OSS could provide a model for screening compounds for treating drug addiction and for the study of behavioral addictions.

Melissa Marino


Sperm torn asunder by mutation

Sperm development, or spermatogenesis, involves coordinated cell division and growth to produce functional, adult male gametes capable of fertilizing eggs. While studying development in the fruit fly Drosophila, Laura Lee, M.D., Ph.D., and colleagues identified a mutant strain – which they named asunder (asun) – whose males are sterile.

In the June 1 Molecular Biology of the Cell, they show that the developing sperm cells of flies lacking the asun gene exhibit a constellation of cellular abnormalities, including loss of nucleus-centrosome attachments. Spermatids and spermatocytes of asun mutants showed a drastic reduction of the dynein-dynactin protein complex on the nuclear surface, suggesting that asun promotes the recruitment of dynein-dynactin to this site, a process required for normal spermatogenesis.

The findings show that the asun gene is a critical regulator of spermatogenesis in Drosophila, and since humans have a putative homolog of asun, the gene may also play a role in human spermatogenesis. And because the gene is expressed throughout the human body, asun may also have functions in somatic cells.

Melissa Marino


We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012