The Peg3 gene is located on chromosome 19q (a region that is often abnormal in gliomas), and is one of a small number of imprinted genes that is expressed exclusively from the father’s copy of the gene under normal conditions. Dr. Johnson has recently shown that the Peg3 protein is involved in p53-mediated neuronal death occurring after radiation or chemotherapy exposure. Recent studies have shown that Peg3 expression is decreased in glioma cell lines due to abnormal genetic changes, and enforced overexpression of Peg3 decreases the ability of these cells to grow and form tumors. Although these data suggest that Peg3 may play an important role in brain tumor biology, none of these observations have been confirmed in patient tumor samples, and the relationship of Peg3 expression to the biology of gliomas in patients is not known. Over the past year, Dr. Johnson and his team have uncovered evidence for an inverse correlation between Peg3 mRNA expression and the degree of malignancy in human gliomas. They are now conducting studies to correlate Peg3 expression in human gliomas with clinical outcome and prognostic variables, and to understand the mechanism by which Peg3 mediates glioma cell death. These studies may thus identify Peg3 as a novel molecular target for the development of more effective therapies for gliomas.

Gliomas (including astrocytomas, glioblastomas, oligodendrogliomas, gangliogliomas and others) are among the most common and difficult to treat of all adult brain tumors. The Johnson laboratory and the Neurosurgical Oncology Laboratory (under the direction of Dr. Peter Black and Dr. Rona Carroll) are working together to unravel the genetic basis for the development of gliomas, and to find more effective treatments for these tumors. They are using cutting edge methods to survey the DNA, RNA and protein expression of brain tumor tissue samples obtained from patients on a genome-wide scale, and have already identified many of the genetic abnormalities that determine glioma development and behavior. Dr. Johnson and the rest of the Neurosurgical Oncology team are now using cellular and molecular biology techniques to determine the mechanisms by which these genetic abnormalities affect the development, growth and response to treatment of human gliomas.

The p53 protein is a transcription factor that promotes growth arrest or cell death after DNA damage due to radiation or chemotherapy exposure. Dr. Johnson and his colleagues are investigating the mechanisms by which DNA damage causes the death of neurons in the brain. In 2004, they reported the use of isotope-coded affinity tag reagents and high throughput mass spectrometry to quantitate changes in the expression of 150 proteins in cortical neurons undergoing DNA damage-induced death. Immunological techniques confirmed several of the changes in protein expression, but microarray analysis indicated that many of these changes were not accompanied by altered mRNA expression. Proteome analysis revealed perturbations in mitochondrial function, free radical production and neuritogenesis that were not observed in p53-deficient neurons. Changes in Tau, cofilin and other proteins recapitulated abnormalities observed in neurodegenerative states in vivo. Additionally, DNA damage caused a p53-dependent decrease in expression of members of the protein kinase A (PKA) signaling pathway. PKA inhibition promoted death in the absence of DNA damage, revealing a novel mechanism by which endogenous downregulation of PKA signaling may contribute to p53-dependent neuronal death. Dr. Johnson and his team are continuing their efforts to dissect the molecular pathways underlying injury-induced neuronal death.

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