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A study of Bax, a gene involved in killing tumor cells

Institution: The Burnham Institute for Medical Research
Investigator(s): Shahrzad Nouraini, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7FT-0100 Award: $75,060
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Cancers associated with tobacco abuse represent the single largest cause of cancer-related mortality worldwide. These smoking-associated malignancies include tumors of the lung, oral cavity, and esophagus.

One of the major causes of cancer is mutations in genes that control cell death. Each day, an average adult produces 50-70 billion new cells in his or her body, necessitating a means for eradicating a corresponding number of cells, otherwise cells accumulate in unhealthy numbers. This cell death is accomplished by the orchestrated actions of a variety of cell survival and cell death genes which do battle with each other on a daily basis.

Mutations caused by exposure to tobacco and smoke upset the delicate balance between the genes that lead to cell death and those that promote cell survival so that tumor cells gain a selective survival advantage and become essentially immortal, living for prolonged periods in the body and gradually accumulating without necessarily dividing any faster than normal. Moreover, once the balance between cell life and death has become upset by changes in these genes, tumors then also become resistant to killing by chemotherapy and radiation.

This proposal seeks to understand the molecular details of how a death gene, called BAX, functions to prevent tumor formation and helps in the killing of tumor cells by radiation and chemotherapy. The information obtained from these investigations will help to establish the foundation of knowledge needed to devise novel strategies for inducing selective killing of tumor cells in patients with cancers of the lung, oral cavity and esophagus.

Final Report
Smoking has been associated with cancers of the lung, oral cavity and esophagus. In a number of cases mutations in genes that control cell death lead to generation of cancer. Exposure to tobacco and smoke can block cell death and lead to generation of tumors by upsetting the balance between the function of genes that prevent cell death and those that inhibit it. Bax is a death promoting gene which normally sits inside the cell at a dormant state. When the signal to die reaches a cell, Bax moves to energy producing structures called mitochondria, and kills cells in two ways: 1) by binding to mitochondria-bound death inhibiting proteins Bcl-2 and Bcl-XL, 2) by poking holes in mitochondria. The objective of my project is to understand the molecular details of how Bax performs these death-promoting activities. The specific aim that has been addressed is how a particular part of Bax participates in the killing activity of this protein.

Specific amino acids in Bax were altered by genetic engineering. The killing activity of altered Bax was tested in two different mammalian cells. The results showed that altered Bax killed cells faster than normal Bax. The reason for faster killing was found to be two-fold; 1) altered Bax moved to mitochondria much faster than wild-type cells, 2) altered Bax bound the death-inhibiting protein Bcl-XL with a much higher affinity compared to wild-type Bax. From these studies we concluded that the role of amino acids that we altered is to keep Bax from localizing to mitochondria and binding to Bcl~L until a signal reaches the cells that tells them it is time to die. Furthermore, the altered amino acids participate in binding {to and inhibiting the death-blocking protein Bcl-XL. This is a very significant role played by these amino acids, since Bax is present in almost all human cells and it would prevent them from surviving if it's localization to mitochondria and binding to anti-apoptotic proteins were not controlled.

Often tumor cells become resistant to killing by chemotherapy and radiation. Since the hyperactive altered Bax can kill cells in the absence of a cell-death signal, we would like to test whether they can make such tumors sensitive to radiation and chemotherapy. This might provide the foundation for a novel strategy to eliminate aggressive tumo
Publications

The putative pore-forming domain of Bax regulates mitochondrial localization and interaction with Bcl-XL
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Nouraini S, Six E, Matsuyama S, Krajewski S, Reed JC ART
Yr: 2000 Vol: 20 Nbr: Abs: Pg: 1604-1615

Yeast as a tool for apoptosis research
Periodical: Current Opinion in Microbiology Index Medicus:
Authors: Matsuyama S, Nouraini S, Reed JC ART
Yr: 1999 Vol: 2 Nbr: Abs: Pg: 618-623