The development of cancer involves somatic genetic changes leading to alterations in the control of cell proliferation. Such alterations result in clonal cell accumulation at the site of tumor origin. However, for a tumor to harm the host through invasion and/or metastasis, the cells must also acquire heritable alterations in the determinants of cell survival. Members of the Bcl-2 family play critical roles in the regulation of cell survival. The Bcl-2 family is comprised of two major subgroups. One subgroup, which includes the oncogenes Bcl-2 and Bcl-xL, prevents cells from undergoing apoptosis. The other major subgroup of Bcl-2-related proteins, which includes Bax and Bak, plays a critical role in the execution of apoptotic cell death. All Bcl-2 family members have been shown to localize to intracellular membranes where they contribute to the regulation of membrane integrity and/or the modulation of membrane transporter function. Although the Bcl-2 family plays a central role in apoptotic cell death, recent evidence suggests that the Bcl-2 family contributes to the regulation of additional cellular processes including: 1) the regulation of ADP-coupled oxidative phosphorylation, 2) intracellular calcium signaling, 3) cell proliferation; and 4) autophagy. Studies over the last five years have not only established a role for Bax and Bak in apoptosis, but led us to develop a variety of cell lines and reagents to explore the molecular basis through which Bcl-2 family proteins regulate these additional cellular processes. In this competitive renewal, we seek to use these reagents to: 1) determine the molecular basis by which Bcl-2 proteins contribute to the regulation of cell proliferation, 2) examine the mechanisms by which Bcl-2 proteins contribute to autophagy versus apoptosis; and 3) investigate how cells can potentially use autophagy to execute programmed cell death. By carrying out these studies, we hope to develop a better understanding of the cell biological processes collectively modulated by the Bcl-2 family. Through a more complete definition of how Bcl-2 proteins contribute to the regulation of cell survival and proliferation, we hope to provide insights that might lead to more successful clinical treatment of tumors that display oncogenic alteration in the balance of pro-apoptotic versus anti-apoptotic Bcl-2 family members. ? ? ?
