Complex Formation with Monomeric ?-Tubulin and Importin 13 Fosters c-Jun Protein Stability and Is Required for c-Jun's Nuclear Translocation and Activity.

ABSTRACT: Microtubules are highly dynamic structures, which consist of ?- and ?-tubulin heterodimers. They are essential for a number of cellular processes, including intracellular trafficking and mitosis. Tubulin-binding chemotherapeutics are used to treat different types of tumors, including malignant melanoma. The transcription factor c-Jun is a central driver of melanoma development and progression. Here, we identify the microtubule network as a main regulator of c-Jun activity. Monomeric ?-tubulin fosters c-Jun protein stability by protein-protein interaction. In addition, this complex formation is necessary for c-Jun's nuclear localization sequence binding to importin 13, and consequent nuclear import and activity of c-Jun. A reduction in monomeric ?-tubulin levels by treatment with the chemotherapeutic paclitaxel resulted in a decline in the nuclear accumulation of c-Jun in melanoma cells in an experimental murine model and in patients' tissues. These findings add important knowledge to the mechanism of the action of microtubule-targeting drugs and indicate the newly discovered regulation of c-Jun by the microtubule cytoskeleton as a novel therapeutic target for melanoma and potentially also other types of cancer.

SUBMITTER: Kappelmann-Fenzl M 

PROVIDER: S-EPMC6895814 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature