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BAG-1, a unique gene involved in smoking-associated cancers

Institution: The Burnham Institute for Medical Research
Investigator(s): Zhihua Xie, Ph.D.
Award Cycle: 1998 (Cycle 7) Grant #: 7FT-0092 Award: $75,060
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
The relationship between tobacco use and cancers of the lung, head & neck, oral cavity, and esophagus is irrefutable. Moreover, tumors associated with tobacco abuse represent the single largest cause of cancer-related mortality worldwide.

Our laboratory has identified a novel gene called BAG-1. The BAG-1 protein is found at high levels in many cancers of the upper respiratory tract and has been linked to an increased risk of cancer spread (metastasis) in patients. A variety of experiments performed in our laboratory and others indicate that BAG- l is a potent regulator of tumor cell growth, which enhances cancer cell division, prolongs cell survival, and increases the ability of tumor cells to spread to other parts of the body.

At present, little is known about how BAG-1 functions, except that it appears to interact with certain other critical proteins involved in tumor cell growth control and probably changes the shape of these proteins so that they are more potent at promoting tumor cell division and spread.

The goal of my proposal is to delineate the molecular details of how BAG- 1 enhances tumor cell growth, survival, and metastasis. This information will provide the foundation necessary for ultimately devising novel strategies for the successful treatment of many of the cancers commonly associated with smoking and tobacco abuse.

Final Report
As cancers progress, they become more and more resistant to therapy and tolerate various stresses. A group of proteins in cells called Heat Shock Proteins (Hsps) helps cells to tolerate stress, including overcoming the damage induced by radiation and chemotherapy. Our laboratory discovered several genes that encode Hsp-binding proteins. We therefore set out to test the hypothesis that these Hsp-binding proteins represent important modulators of Hsp activity and to explore the effects of these proteins on other proteins known to be relevant to cancer. Our studies revealed that these Hsp-binding proteins, called "BAG" family proteins are indeed potent modulators of Hsp function. We found that BAG family proteins are commonly present at high levels in human cancers, including lung cancer cells.

Our studies provided detailed 3-dimensional structural information about the BAG1 protein, suggesting ways to design drugs that overcome the protect effect of this protein on cancer cells.

An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Takayama S, Xie Z, Reed JC ART
Yr: 1999 Vol: 274 Nbr: Abs: Pg: 781-786

Characterization of BAG-1 interactions with Hsc70 molecular chaperones
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Stuart JK, Myszka DG, Joss L, et al ART
Yr: 1998 Vol: 273 Nbr: Abs: Pg: 22506-22514

The HIV viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore.
Periodical: Journal of Experimental Medicine Index Medicus:
Authors: Jacotot E. et al. ART
Yr: 2000 Vol: 191 Nbr: 1 Abs: Pg: 33-45

Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3.
Periodical: Science Index Medicus:
Authors: Li H, et al. ART
Yr: 2000 Vol: 289 Nbr: Abs: Pg: 1159-1164