September 19, 1997

Researcher probes gene that may induce cell death

Researcher probes gene that may induce cell death

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Dr. Elizabeth Yang (right) and research assistant Anuja Chattopadhyay are studying a powerful cell-death inducer. (Photo by Donna Marie Jones)

The area of programmed cell death has become fertile ground for researchers seeking to understand how interruptions in a cell's natural "program" to die can lead to cancer and make tumors resistant to treatment.

A new investigator at the Vanderbilt Cancer Center and Vanderbilt Children's Hospital is studying a powerful cell-death inducer she identified during her fellowship with an eye toward its potential role in cancer.

"I have been studying how this gene worked and determined that it caused cell death," said Dr. Elizabeth Yang, assistant professor of Pediatrics in the division of Pediatric Hematology/Oncology. "Now I'm focusing on how the gene does that."

The gene, called BAD, is among a family of homologous genes related to apoptosis, or programmed cell death.

The first of these genes, called BCL2, was identified in adult B-cell lymphomas by Dr. Stanley Korsmeyer at Washington University in St. Louis. BCL2 is involved in a very common chromosome translocation (14,18) that is characteristic of adult follicular lymphomas, Yang said.

"The gene is overexpressed in those lymphomas and prolongs cell survival," Yang said.

Other genes were subsequently identified. The second, BAX, is the cell death-promoting counterpart to BCL2. The third, BCLX, is a cell death inhibitor that was first identified in chicken lymphocytes.

Then Yang identified BAD, so named because it is such a powerful death inducer, she said.

"We now hope to understand the mechanism by which these genes work," she said. "Our work now is focused on basic science questions, and the next step is see how BAD is related to disease."

The link between cancer and the natural process by which cells die is a logical one because cancer is a group of diseases characterized by renegade cells that circumvent the normal mechanisms for cell growth and differentiation.

"There's evidence that when cells do not die when they should die, there is a propensity to develop cancer," Yang said. "You have cells that have sustained mutations ‹ critical hits that otherwise should be eliminated from the organism. But because of the inability to undergo programmed cell death, those cells hang around and accumulate more and more mutations."

The ability of cells to undergo programmed cell death is also related to the cells' response to chemotherapy or radiation, she said.

"Cells that do not die when they are met with a chemical toxin or radiation because of disturbed pathway to cell death become resistant," she said. "The cells which readily undergo cell death have a greater chance of responding to therapy."

Yang, who joined the Vanderbilt faculty last spring, is studying BAD in cell cultures. Her lab and others have recently noted that BAD and its family of genes have effects on cell cycle functions as well as cell death.

"I'm interested in figuring out whether the cell cycle and the cell death effects are related," Yang said. "We have found that if we block cells in cell cycle so that they are no longer dividing, and then we let them divide again, the cells that overexpress BCL2 or BCLX tend to return to division much more slowly."

BAD and BAX, on the other hand, have the opposite effect on the cell cycle, Yang said.

"When BAD is overexpressed, the cell cycle cannot arrest efficiently," she said. "The cells continue to cycle when they shouldn't.

"These genes have opposite effects on cell death and opposite effects on cell cycling, but we have to determine for certain whether these two functions are mechanistically linked. It could be that these genes have two different functions that are not directly related. If we could figure out whether they are interdependent, I think it will help us understand more about how cell death works in general."

Another area that Yang's lab is focusing on is differentiation, or specialization, of cells and the relationship between their specialization and cell death.

"Cells that are terminally differentiated tend not to divide, particularly epithelial cells," Yang said. "They eventually will die. They don't renew themselves. Once, for instance, your skin cells die and slough off, those cells are gone. You get more skin cells, but those come from the stem cell layer. It appears that a commitment to cell differentiation may be a commitment to cell death, so there's some relationship between the two.

"I'd like to explore that system because the BAD gene seems to be expressed in the layer of skin cells where epidermal cells are first committed to becoming keratinocytes."

Yang completed her medical degree and her Ph.D. in cancer biology at Stanford University. After a residency in pediatrics at Massachusetts General Hospital in Boston, she served a fellowship in pediatric hematology/oncology at Washington University just before coming to Vanderbilt.

Yang, who also sees patients in addition to her research work, says she was attracted to the Vanderbilt Cancer Center and Vanderbilt Children's Hospital because of the vibrancy of the programs and the commitment to supporting and promoting junior investigators.

"I wasn't interested in doing just basic research," she said. "I want to make some clinical use of the knowledge from the lab. I hope I can span the two."