Abstract
In order to understand how oxidative stress signal transduction pathways evolve, we analyzed the molecular evolution of the p38 MAPK (p38K) gene family across the genus Drosophila. p38K family genes play a vital role in oxidative stress resistance and are also important for organismal development and immunity. We find that the p38Ka and p38Kb genes are highly conserved across the genus and that p38Kc is more recently evolved. We further find that the p38Kb genomic locus includes conserved binding sites for the AP-1 and lola-PT transcription factors. Accordingly, over-expression of either AP-1 or lola-PT in D. melanogaster is sufficient to induce transcription of p38Kb under normal conditions, while under oxidative stress only lola-PT over-expression was able to induce p38Kb transcription. In addition, exposure to oxidative stress results in increased p38K protein levels in a number of species. These increased levels are associated with an increased resistance to oxidative stress across species. We also find that the presence of a lola-PT binding site in the p38Kb locus is predictive of the species’ survival in response to oxidative stress. Through our comparative genomics approach, we have identified biologically relevant transcription factor binding sites that regulate the expression of p38Kb and are associated with resistance to oxidative stress. These findings reveal a novel mode of regulation for p38 MAP Kinases and suggests that transcription may play as important a role in p38K mediated stress responses as post-translational modifications.
Significance Statement Organisms encounter a variety of environmental stresses such as oxidative stress throughout their lifetime. Therefore, organisms have evolved a number of mechanisms to combat these stresses. In order to understand how these mechanisms evolved, we have compared the genomes of a diverse set of species across the genus Drosophila to examine the p38 MAPK stress response gene family. Our analysis was able to successfully predict transcription factors that not only regulate our target gene, p38Kb, but do so under different conditions to ensure an appropriate stress response. Therefore, we find that in addition to post-translational regulation, transcriptional regulation of signaling pathways may also play an important role in how organisms are able to adapt to stressful environments or respond to stress conditions as they arise. Furthermore, our comparative genomics approach may be utilized to identify transcriptional regulators of other highly conserved signaling pathways.
Footnotes
Author contact information has been updated and a Significance Statement has been added. We have changed the title and added additional information to the abstract, significance statement, introduction, and discussion.