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Aliquots ó research highlights from VUMC laboratories

9/16/2010 - 
BRCA1 locale key for cell death

Mutations in the BRCA1 gene have been implicated in the development of inherited breast cancers. The BRCA1 protein participates in processes including repair of DNA breaks, DNA replication, and cell death. BRCA1 moves between the cell nucleus and cytoplasm, and Fen Xia, M.D., Ph.D., and colleagues have proposed that active “shuttling” between cellular compartments may regulate BRCA1’s functions.

The researchers report in the Aug. 1 issue of Cancer Research that BRCA1 must be in the nucleus to repair DNA breaks. They found that confining BRCA1 to the cytoplasm of human breast and colon cancer cells enhanced the cytotoxicity (killing power) of radiation or the chemotherapy drug cisplatin. This enhanced cytotoxicity depended on the shuttling of BRCA1 to the cytoplasm, but not on its DNA repair activities.

The findings suggest a novel role for BRCA1 nuclear/cytoplasmic shuttling in the regulation of cell death processes following DNA damage. BRCA1 shuttling may provide a marker to predict tumor response and a novel target to sensitize cancer cells to DNA damage-based therapies.

— Leigh MacMillan


Hedgehog hunted in kids’ brain tumors



Pilocytic astrocytoma, the most common type of pediatric brain tumor, has an excellent 10-year survival rate and is often viewed as a benign lesion. However, survival and progression-free survival rates fall over time and survivors often suffer later consequences related to disease or treatment.

Sarah Rush, M.D., Michael Cooper, M.D., and colleagues analyzed activation of the Hedgehog (Hh) pathway – which has been implicated in the growth of other types of brain tumors – in pilocytic astrocytomas from patients aged 1 to 22 years. They found that the Hh pathway is operational in 45 percent of sporadic pilocytic astrocytomas and activated to a greater extent in tumors from younger patients with more aggressive pathological features. They also demonstrated that expression of Hh pathway signal transduction components correlated with the expression of a marker for cell proliferation.

The study, which was featured on the cover of the August issue of Neuro-Oncology, suggests that Hh activation is common in these tumors and may be associated with younger age at diagnosis and poorer outcome.

— Melissa Marino


Connecting food and mood



Patients with metabolic disorders, such as diabetes and obesity, are more likely to have mental disorders including depression and schizophrenia. To explore this connection between food and mood, Aurelio Galli, Ph.D., and colleagues are studying how insulin signaling regulates the function of the norepinephrine transporter (NET). NET controls norepinephrine signaling in central brain circuits involved in attention, mood and memory, and in autonomic nervous system circuits that regulate blood pressure.

The researchers report in the Aug. 25 issue of the Journal of Neuroscience that acute insulin treatment – in mouse brain slices and isolated spinal neurons – decreases NET levels on the cell surface and that the insulin-signaling protein Akt is required for NET regulation. In mice with diabetes (induced by a toxin), they found changes in Akt activity and altered NET levels in the brain. The findings provide a link between abnormal insulin signaling in the periphery and regulation of NET function and neurotransmitter levels in the brain.

— Leigh MacMillan


Excess editing in RNA



Mice with highly edited serotonin 2C receptor RNA may represent a novel model for Prader-Willi syndrome (PWS), a developmental disorder characterized by cognitive deficits and excessive eating, Ronald Emeson, Ph.D., and colleagues report in the August issue of Neurobiology of Disease.

RNA editing subtly alters RNA sequences before their translation into proteins. RNA transcripts encoding the serotonin 2C receptor (which is involved in feeding, mood disorders, and sleep regulation) undergo five editing events, which give rise to 24 different protein isoforms.

The researchers generated mice expressing only the fully edited form of the receptor. These mice showed reduced food consumption and failure to thrive as newborns, but began to eat excessively after weaning (a pattern that corresponds to features of PWS in humans). Since PWS is caused by an abnormality on the long arm of chromosome 15, mutations in the serotonin 2C gene (which lies on the X chromosome) may represent the first locus outside of chromosome 15 linked to this syndrome.

— 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
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April 27, 2012
April 13, 2012
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