Scientists determine how tumor gene controls growth

October 31, 2005

ATLANTA -- Researchers at Emory University School of Medicine and their colleagues have discovered a genetic mechanism that controls cellular growth in the fruit fly Drosophila melanogaster, and believe it likely that a similar system may be at work in normal and cancerous human cells. The findings appear in the November issue of the journal Developmental Cell. Ken Moberg, PhD, assistant professor of cell biology at Emory University School of Medicine, is the lead and corresponding author of the paper. Moberg joined the Emory faculty in 2003, and most of the work described in the paper was done in his Emory lab. The senior author is Iswar K. Hariharan, professor of cell and developmental biology at the University of California, Berkeley.

The Emory and Berkeley researchers have uncovered important details about how mutational inactivation of the Drosophila version of Tumor Susceptibility Gene 101 (Tsg 101) causes cells to overgrow, leading to organ hypertrophy and tumor-like growths. Scientists first identified the human Tsg101 gene in the mid-1990s based on its ability to control the growth of cells in a culture dish, but little has been learned since then about how it does this. "The work that was done ten years ago strongly implicated Tsg101 as a growth regulatory gene, but how it works has remained largely obscure," Dr. Moberg says,

In the interim, the Tsg101 gene has become better known for its role in "endosomal sorting," the process by which proteins are shuttled to and from the cell surface, but researchers had little luck connecting this property to the gene's potential role in human cancer. "People didn't really understand how the two would fit together," Moberg says.

Moberg's findings show that there is in fact a direct link between the "sorting" and growth regulatory roles of Tsg101. Moberg and his team determined that defective sorting of the Notch receptor, a protein that sends signals throughout the cell, is key to the biology of Tsg101 mutant cells. Endosomal sorting is an important way in which cells control Notch activity, and when Tsg101 mutant cells are unable to correctly sort Notch protein, it becomes hyperactivated, and causes excess tissue growth.

In addition, Moberg discovered that the mechanism through which Tsg101 controls cell growth is non-cell-autonomous, meaning that mutated cells cause surrounding normal cells to overgrow, resulting in tumor-like growths made up of a heterogeneous mix of cells, some normal, some mutated.

Before now, most mutations that cause cancer have been found to act cell-autonomously, that is the mutant cells themselves overgrow and form a genetically homogeneous tumor. For that reason, Moberg comments, "this is a very surprising and somewhat novel mechanism for a growth regulatory gene." He adds "these new findings suggest the possibility that, in fact, some as yet unidentified subset of human cancers might actually be composed of a mixture of normal cells and cells with mutations in genes like Tsg101."

While the research so far has been limited to Drosophila, Moberg expects his research to prompt a renewed focus on the role of the Tsg101 mutations in human cancers. "I'm hoping this will eventually translate into a better understanding of the role of the human version of the gene in disease," he says.

In addition, drugs already available that target Notch may find new uses if human Tsg101 is found to control growth in a similar way to fruit fly Tsg101. As Moberg says, "It may turn out that some of these drugs may actually be clinically useful in treating a hypothetical class of human cancers that harbor mutations in Tsg101."

After presenting the data at an international Drosophila conference, Moberg found out that two other labs were coming to very similar conclusions about another fruit fly "endosomal sorting" gene called vps25. The three groups agreed to co-submit their work for publication. Consequently, the Tsg101 paper is being published in Developmental Cell together with two articles about vps25 from the labs of Stephen Cohen, a senior scientist at the European Molecular Biology Laboratory in Heidelberg, Germany, and David Bilder, assistant professor of cell and developmental biology at the University of California, Berkeley.

Emory University Health Sciences Center

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