Tubulin mRNA stability is sensitive to change in microtubule dynamics caused by multiple physiological and toxic cues

Abstract

The localization, mass, and dynamics of microtubules are important in many processes. Cells may actively monitor the state of their microtubules and respond to perturbation, but how this occurs outside mitosis is poorly understood. We used gene expression analysis in quiescent cells to analyze responses to subtle and strong perturbation of microtubules. Genes encoding -, {beta}, and {gamma}-tubulins, but not {delta}- or {varepsilon}-tubulins, exhibited the strongest differential expression response to microtubule-stabilizing versus destabilizing drugs. Q-PCR of exon versus intron sequences confirmed that these changes were caused by regulation of tubulin mRNA stability and not transcription. Using tubulin mRNA stability as a signature to query the GEO database, we find that tubulin genes respond to toxins known to damage microtubules. Importantly, we find many other experimental perturbations, including multiple signaling and metabolic inputs that trigger tubulin differential expression, suggesting their novel role in the regulation of microtubule cytoskeleton. Mechanistic follow up confirms that one important physiological signal, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activity, indeed regulates tubulin mRNA stability via changes in microtubule dynamics. We propose that that tubulin gene expression is regulated as part of many coordinated biological responses, with wide implications in physiology and toxicology. Furthermore, we present a new way to discover microtubule regulation using genomics.