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

• Main Authors: Melanie Kappelmann-Fenzl, Silke Kuphal, Rosemarie Krupar, Dirk Schadendorf, Viktor Umansky, Lily Vardimon, Claus Hellerbrand, Anja-Katrin Bosserhoff
• Format: Article
• Language: English
• Published: MDPI AG 2019-11-01
• Series: Cancers
• Subjects: ap1; c-jun; transcription factor; tubulin; importin
• Online Access: https://www.mdpi.com/2072-6694/11/11/1806

Microtubules are highly dynamic structures, which consist of α- and β-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 α-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 α-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.