A team headed by Drs. Robin Hiesinger and Hugo J. Bellen at Baylor College of Medicine in Houston have unraveled a piece of that puzzle by finding a gene that plays a key role in brain wiring. A report on their work appears today in the journal Neuron.
"We were surprised to find an exocyst mutant having such specific defects," said Bellen, professor of molecular and human genetics at BCM. "The cell biological basis of brain wiring is largely unknown. We are happy to have a new handle on an old problem."
Using sophisticated genetics applied to the brain of the fruit fly, Drs. Sunil Mehta and Hiesinger found a gene named sec15 that is required for nerve cells to make appropriate choices of targets on which to act.
The Sec15 protein is part of a protein complex (the exocyst) which is known to be required for secretion (or exocytosis) of vesicular compartments in yeast. Vesicular compartments are small organelles that transport proteins from one site to another in the cell.
Neurons in the fly brain that lack sec15 not only display aberrant wiring patterns, but also show misplacement of proteins required for correct nerve cell contact choices.
Most of these cell contact proteins were previously known to display highly dynamic expression patterns in both time and space, but how they are put at the right time and at the right place remains to be shown. This study answers part of that question.
Others who participated in this work include Dr. Mike Crair of BCM, Drs. R. Grace Zhai, Karen L. Schulze, Patrik Verstreken, Yu Cao and Yi Zhou from the Howard Hughes Medical Institute at BCM and Drs. Slobodan Beronja and Ulrich Tepass from the University of Toronto.
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In testing their hypothesis, Whang and his co-authors inhibited HER-2 activity in two laboratory experiments involving human cancer cells. In the first, they used an artificial antibody to HER-2 delivered directly into the cells via a modified virus. In the second, they used an experimental drug that specifically inhibits HER-2 tyrosine kinase activity. The oral drug lapatinib (GlaxoSmithKline) is currently in an advanced clinical trial involving patients whose breast cancer is driven by HER-2.
In both experiments, tyrosine kinase activity and androgen receptor function were largely derailed.
"We discovered that inhibition of HER-2 strongly inhibits proliferation of prostate cancer cells and the function of androgen receptor," Whang said.
To properly carry out its function, the androgen receptor protein binds specifically to the regulatory DNA sequence of the genes regulated by androgens such as testosterone, he said. "And we have shown that inhibition of HER-2 impairs the androgen receptor function at this step of binding to the DNA sequence of critical genes such as prostate specific antigen."
The implication of this work, he added, is that HER-2 is important and necessary for prostate cancer viability and progression.
"This provides the rationale for initiating a clinical trial of this novel drug inhibiting HER-2, which is being planned for patients within several months," Whang said. "I envision this drug becoming one of several that could be used in combination with other specifically targeted drugs to prolong the lives of prostate cancer patients."
UNC co-authors with Whang include postdoctoral researchers Drs. Yuanbo Liu and Samarpan Majumder; Wesley McCall, research technician; Dr. Carolyn Sartor, assistant professor of radiation oncology; Dr. James Mohler, professor of surgery; and Dr. Shelton Earp, director, UNC Lineberger. Dr. Christopher Gregory, former UNC assistant professor of pathology and another co-author, is now with Voyager Pharmaceutical Corp. in Raleigh.
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