In the Bratton laboratory, we are primarily interested in two basic areas of research: apoptosis (programmed cell death) and autophagy (self-cannibalism). Apoptosis is critical for normal
development in multicellular organisms from flies to humans, and it works in concert with cell division to maintain the normal size and function of adult tissues. Diseases associated with increased
rates of apoptosis, include neurodegenerative
disorders (Alzheimer's Disease and Parkinson's Disease), AIDS, myelodysplastic syndromes, and ischemic injury (stroke and myocardial infarction), whereas those associated with inhibition of
apoptosis, include autoimmune diseases and cancer. In fact, defective apoptosis is a hallmark of cancer and a major cause of resistance during cancer therapy. Autophagy, on the other hand, is
primarily a cell survival rather than a cell death process. In cells deprived of growth factors or nutrients, intracellular proteins and even entire organelles are broken down and proteolytically
digested within lysosomes in order to provide energy and macromolecules for essential biosynthetic
pathways. Autophagy therefore plays an important role during tumorigenesis, as it allows early solid tumors to survive prior to vascularization (angiogenesis), and it promotes chemoresistance by
allowing tumor cells to remove damaged proteins and organelles. Finally, emerging evidence suggests that cross-talk exists between
apoptotic and autophagic pathways, in that established regulators of apoptosis, such as the tumor suppressor p53 and antiapoptotic Bcl-2 family members, also regulate autophagy.
There are currently five ongoing projects in the laboratory that focus on the general regulation of apoptosis and/or autophagy in cancer:
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- Caspase-activating complexes: Most toxicants induce apoptosis by triggering the activation of caspases (cysteinyl aspartate-specific proteases). Initiator caspases
association with specific adapter proteins, and in turn, activate effector caspases that cleave cellular proteins and dismantle the cell. Thus,
caspases are activated through unique signal transduction pathways, and our general goal is to understand, in molecular detail, how these caspases are activated and how their activities are
modulated. We are particularly interested in a multimeric complex known as the apoptosome. This large complex--composed of seven Apaf-1
(apoptosis protease-activating factor-1) proteins and formed in response to mitochondrial stress--binds to the initiator caspase-9 to form a holoenzyme that subsequently activates the effector
caspases-3 and -7. We are currently studying the regulatory mechanisms that control the activity of this complex in vitro and in vivo.
- Inhibitor of apoptosis (IAP) proteins and IAP antagonists: IAPs are important antiapoptotic proteins present throughout nature. In humans and rodents, at least one family
IAP), is an established inhibitor of caspases-9, -3 and -7. However, it remains unclear how other family members suppress apoptosis.
We are currently investigating the mechanisms whereby other IAPs, such as cellular IAP1 (cIAP1) and cIAP2, as well as Drosophila IAP-1 (DIAP1) and DIAP2,
suppress apoptosis in human and fly models
of cell death. The fly IAP antagonists, Reaper, Hid (head involution defective), Grim, Sickle, and dOmi, are thought to induce
apoptosis during development by antagonizing DIAP1. Recent studies in our laboratory and others, however, suggest that these IAP antagonists may promote cell death through mechanisms that do not
involve antagonism of DIAP1 per se. Thus, we are actively pursuing these alternative pathways to death.
- Heat shock-induced apoptosis: Hyperthermia or heat shock therapy is currently being utilized in phase II/III clinical trials, either alone or in combination with radiation
or chemotherapy, for
the treatment of various cancers. Unfortunately, though intense heat shock induces apoptosis, the underlying mechanisms remain controversial
and unclear. We have recently shown that heat shock induces caspase-dependent apoptosis, but does so through mechanisms that do not require any of the known initiator caspases or their activating
complexes. We are currently working to identify the mechanisms responsible for heat shock-induced apoptosis, including the
identification and characterization of the apical protease(s) responsible for initiating the caspase cascade.
- TRAIL-induced apoptosis and resistance in prostate cancer: Tumor cells are normally removed from the body, in part, through the activation of death receptors
Fas/CD95 or death receptors-4 and 5 (DR4/5). These receptors are activated by their cognate ligands, FasL and Tumor necrosis factor-
related apoptosis-inducing ligand (TRAIL), respectively, and TRAIL has potential therapeutic value due to its capacity to induce apoptosis selectively in cancer cells. In fact, recombinant TRAIL
and agonistic antibodies to DR4/5 are currently in clinical trials for the treatment of various cancers. Unfortunately, ~50% of tumors exhibit
resistance to TRAIL. We are investigating the primary mechanisms of TRAIL resistance in prostate cancer using both in vitro and animal models.
- p38 MAPK-dependent regulation of death receptor and autophagic trafficking: Often upregulated in cancer and activated in response to growth factor stimulation, p38
kinases (MAPKs) control secretion and trafficking of various cell surface receptors and transporters. Recent studies suggest that p38
MAPKs may also regulate autophagy through unknown mechanisms. We are examining the role(s) of p38 MAPKs in regulating the intracellular trafficking of death receptors, such as tumor necrosis factor
1 (TNFR1). Moreover, we are working to unravel the specific mechanisms through which p38 MAPKs suppress autophagy
and determine the interrelationships between death receptor and autophagic signaling.
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