November 13, 2009
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No bad luck here in unraveling new genetic and proteomic links in disease…
Gene Variants Linked to Hearing Loss: A genetic link to hearing loss in children who are being treated with the chemotherapy drug, cisplatin, has been identified. Cisplatin is a widely used anti-cancer drug but one of the harmful side effects is hearing loss experienced by over 60% of young cancer patients. In the study by Dr. Michael Hayden’s team (Child & Family Research Institute, Vancouver), they analyzed 220 drug metabolism genes and found variants in two particular genes that are associated to hearing loss in children – one gene is called TPMT (thiopurine methyltransferase) and the other is COMT (catechol-O-methyltransferase). With this information, doctors can perform genetic tests to determine the patient’s susceptibility to developing hearing loss and seek alternative treatment if necessary. Further studies investigating how these enzymes contribute to cisplatin-induced hearing loss could lead to drugs to counteract these effects while receiving the benefits of cisplatin therapy. The study appears in this week’s Nature Genetics.
The Missing Links in 5q- Syndrome: In patients with 5q- syndrome, a portion of chromosome 5 is deleted and the result is abnormal function of bone marrow cells leading to severe anemia. We now know what is missing in this region of chromosome 5 that have key roles in maintaining the integrity of bone marrow cells. In the investigation reported in Nature Medicine, Dr. Aly Karsan at the University of British Columbia and BC Cancer Agency discovered that two microRNAs (miRNAs), miR-145 and miR-146a, are lost in 5q- syndrome. MicroRNAs are short, single-stranded RNA that act to down regulate expression of specific target genes. The targets of miR-145 and miR-146a are two proteins called TIRAP and TRAF6, which play important roles in immune signalling but should be turned off in hematopoietic stem/progenitor cells during blood cell development. In support of their hypothesis, the researchers demonstrated in mice that forced expression of TRAF6 results in a condition that is similar to human 5q- syndrome.
Cancer Genes Now Linked: Researchers at Queen’s University studying C. elegans worms identified a connection between two genes involved in cancer. PTEN is a tumour suppressor and loss of function mutations are known to be involved in a number of cancers. Eph receptor signalling is required in developmental pathways and its expression level is elevated in some cancers. New evidence now connects PTEN and Eph receptors in development and cancer. The research led by Dr. Ian Chin-Sang’s team demonstrated an inverse relationship where Eph receptors can phosphorylate and downregulate PTEN. Conversely, PTEN activity can modulate Eph receptor signaling. If there is an imbalance in this relationship, then the (negative) effects may be amplified quickly. The study report appears in the current issue of Developmental Cell.
Determining Thryoid Hormone Receptor Complexes in Yeast: This is a neat genetic array assay using yeast as a simple model system to unravel co-regulators in thyroid hormone receptor (TR) activity. A yeast strain expressing TR was systematically crossed with each of 384 yeast strains bearing deletions of known genes. From this unbiased assay, researchers identified four genes that are deemed essential for thyroid hormone function and are also conserved in humans. Dr. Paul Walfish (Toronto Mount Sinai Hospital) and his team focused on one of these genes, CCR4. They validated its role in thyroid hormone receptor action by performing a series of CCR4 expression and deletion analyses in cultured human cells and proved its association with TR in response to thyroid hormone. Details of their findings appear in the early online edition of The Proceedings of the National Academy of Sciences.
FGFR3 Phosphorylation Network in Disease: An emerging field in proteomic studies is large-scale phospho-proteomic analyses using mass spectrometry to map signalling pathways. This technique was applied to define the FGFR3 phosphorylation network in multiple myeloma and other cancers. The researchers also demonstrated in their work the ability to quantitatively detect the upregulation or downregulation of over 60 phosphorylation sites on proteins that either responded to growth factor stimulation or inhibition by the pharmacologic drug PD173074. One could apply this general method for pharmacodynamic monitoring of any drug inhibitor to fully understand its implications in the cell. Dr. Michael Moran’s research team at the Hospital for Sick Children and University of Toronto published their report in this week’s Proceedings of the National Academy of Sciences.