Scientists at Emory University School of Medicine, in research with mice, now have discovered more specific information about how this inherited expansion of a normal repeated DNA sequence alters gene expression. The research is reported online in the journal Nature Neuroscience.
The inherited diseases caused by an abnormal number of glutamine repeats (generally, more than 37) are known as polyglutamine, or PolyQ diseases. The diseases lead to a progressive degeneration of nerve cells usually affecting people later in life. Although these diseases share the same abnormal expansion of the repeated glutamine sequence and some symptoms, the repeats for the different PolyQ diseases occur in genes on different chromosomes.
The scientists found that abnormal glutamine repeats interfere with the function of an essential transcription factor called TBP (TATA-box binding protein). In turn, the expanded polyQ sequence alters the interaction of TBP with other transcription factors, leading to neurodegeneration. Transcription is the process by which the genetic code in the DNA sequence is first transcribed into RNA. The RNA is subsequently translated into a protein.
"Our study has a broad impact for understanding transcriptional regulation of gene expression as well as the pathogenesis of neurodegeneration caused by expanded polyglutamine proteins," says Xiao-Jiang Li, MD, PhD, Distinguished Professor of Human Genetics in Emory University School of Medicine and the paper's senior author.
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Expression of the gene was compared in 18 pairs of human non-small cell lung cancer and adjacent normal tissue. In 11 cases, or 61 percent, the tumors had lower levels of GPRC5A messenger RNA than did the nearby normal tissue. Two had higher levels of expression in the tumor and one pair had similar levels in both tissues. Four had no expression in either sample.
Next, the team used gene expression profiling with a microarray to compare 186 lung tumors to 17 normal control tissues. The four tumor types all had a fraction of the GPRC5A gene expression shown in the normal cells: adenocarcinoma 46.2 percent; squamous cell carcinoma at 7.5 percent; small-cell lung cancer at 5.3 percent; and carcinoid at 1.8 percent.
Finally, they inserted the GPRC5A gene back into lung cancer cell lines in a laboratory experiment, suppressing colony formation of human lung cancer cells by 91 percent in two cell lines.
"These findings suggest that GPRC5A can suppress lung cancer development in humans as well as mice," Lotan says.
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