Investigating the Role of Caspase-2 as a Tumor Suppressor
The main project in our lab focuses on a pro-apoptotic protease called caspase-2. Despite being the most evolutionarily conserved caspase, the role of caspase-2 in apoptosis remains unclear. Work from my lab and others have shown that caspase-2 plays key roles in non-apoptotic functions including cell division and the regulation of genomic instability. Consistent with these non-apoptotic roles, caspase-2 has been shown to act as a tumor suppressor in a number of murine cancer models. Our goal is to determine the upstream regulatory signals and the downstream functional consequences of caspase-2 activation and how these mechanisms ultimately lead to tumor suppression. We recently reported on the mechanism of caspase-2 following DNA damage, identifying a novel caspase-2 activating complex in the nucleolus that requires the nucleolar protein nucleophosmin (NPM1). We are currently interrogating the assembly and regulation of this novel complex as well as its downstream functions in the DNA damage pathway.
Supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number R01GM121389 and the Children’s Leukemia Research Association
Mechanisms of Inflammatory Caspase Activation
Since the description of the first inflammasome over 10 years ago, it has become abundantly clear that correct assembly and regulation of these multi-protein signaling complexes is critical to prevent uncontrolled inflammation. Inflammasomes mediate inflammation in both infectious and sterile conditions underlying the pathogenesis of many diseases and disorders ranging from sepsis to sickle cell disease. A number of distinct inflammasomes exist but they all converge on a subset of the caspase family known as inflammatory caspases that includes caspase-1, -4, -5, -11 and -12. Caspase-1 is an initiator caspase, activated by proximity-induced dimerization following recruitment to inflammasomes and is required for the maturation of the proinflammatory cytokines, interleukin-1β and interleukin-18. The contribution of the remaining inflammatory caspases to inflammasome activity remains unclear. We have developed imaging techniques to specifically measure inflammatory caspase interactions at the level of the inflammasome in living cells. We are using these approaches to uncover novel mechanisms of inflammatory caspase activation.