Being trained as a developmental biologist, I am taking genetic and biochemical approaches to analyze key signaling pathways that orchestrate development, yet are co-opted during oncogenesis. As these key pathways are evolutionarily conserved, I use the fruit fly, Drosophila melanogaster, to study various aspects of the Jun N-terminal kinase (JNK) signaling pathway and how it influences the induction of programmed cell death in response to genotoxic stress.
Cell fate decisions depend on the duration and/or peak amplitude of JNK activation; thus, strict modulation of JNK activity directs phenotypic decisions. The main antagonists of JNKs are the MAPK phosphatases (or MKPs). At least nine distinct genes exist in vertebrates. However, selective inactivation of these genes fails to affects organism viability, suggesting functional redundancy exists between vertebrates MKPs. In contrast, I have demonstrated that inactivation of Puckered (Puc), the sole JNK-specific MKP in Drosophila, induces apoptosis. Thus, Puc is required autonomously in all cells to promote cell viability by restraining basal JNK activity (anti-apoptotic).
Furthermore, I have demonstrated that JNK signaling plays an important role in genotoxic stress-induced apoptosis. g-irradiation stimulates both JNK activity and puc expression in a p53-dependent manner, whereas JNK-dependent apoptosis can be suppressed by p53 inactivation. Nevertheless, we understand very little about the integration of these two signaling pathways. To this end, one focus of my lab is to define the function relationships between the p53 and JNK signaling pathways.
Finally, I have demonstrated that Puc-mediated antagonism of JNK is required during normal development. However, if cell death is prevented, JNK activation can trigger tissue overgrowth. Thus, Puc is a key regulator of cell proliferation and functions similar to a tumor suppressor gene during development. To this end, I am using Drosophila genetics to characterize both the signals that promote JNK activation as well as the downstream effectors that support proliferation in the absence of apoptosis.