David M. Hockenbery, MD
Associate Professor, Medicine2
Associate Member, Clinical Research and Human Biology3 dhockenb@fhcrc.org
Researchers in my laboratory study the genetic and biochemical mechanisms of programmed cell death, or apoptosis, in a variety of experimental systems. Normal cell death occurring during development and following terminal differentiation has typical morphologic and biochemical features collectively termed apoptosis. One regulator of this process is the bcl-2 oncogene, which blocks apoptosis in vitro and in vivo and appears to control the timing of cell death in many cell lineages. We have recently identified that an 'abortive' mitochondrial proliferation takes place in apoptosis, culminating in autophagy of nascent mitochondria and ultimately mitochondrial swelling and lysis. Bcl-2 acts as a negative regulator of mitochondrial proliferation during apoptosis.
Our laboratory recently set up a screening assay using isogenic cell lines for compounds that selectively kill cells with high levels of Bcl-xL that are resistant to multiple chemotherapeutic agents. We identified antimycin A, an inhibitor of electron transport, with this screen. Antimycin A causes rapid apoptosis with mitochondrial swelling only in cells that express high levels of Bcl-xL. We are exploring the structural basis of antimycin binding to Bcl-xL to determine whether antimycin can be a lead compound for targeted chemotherapy of Bcl-xL expressing tumors.
