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Nuclear ß_II-Tubulin Associates with the Activated Notch Receptor to Modulate Notch Signaling

¹ Graduate Institute of Cell and Molecular Biology and ² Graduate Institute of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan; ³ Department of Dermatology, Taipei Municipal Wan-Fang Hospital-Affiliated with Taipei Medical University, Taipei, Taiwan; ⁴ Department of Life Science, National Chung Cheng University, Chia-Yi, Taiwan; ⁵ Department of Biochemistry, Taipei Medical University, Taipei, Taiwan; and ⁶ Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan

The Notch signal pathway plays important roles in proliferation, apoptosis, and differentiation. Abnormalities in Notch signaling are linked to many human diseases. After ligand binding, Notch signaling is activated through the cleavage of Notch receptors to release and translocate the Notch intracellular domain into the nucleus. The Notch1 receptor intracellular domain (N1IC), the activated form of the Notch1 receptor, can modulate downstream target genes via C promoter-binding factor 1–dependent and -independent pathways. To further dissect the Notch1 signaling pathway, we screened the N1IC-associated proteins using a yeast two-hybrid system and identified nuclear ß_II-tubulin as a candidate for the N1IC-associated proteins. It was suggested that the presence of ß_II-tubulin in nuclei might be correlated with the cancerous state of cells. However, the function of ß_II-tubulin locating in the nucleus still is unknown. Herein, we show that the complex of - and ß_II-tubulin is associated with N1IC in cancer cells by a coimmunoprecipitation analysis. The ankyrin domain of the Notch1 receptor alone was sufficient to associate with ß_II-tubulin. Furthermore, - and ß_II-tubulin were localized in the nucleus and formed a complex with N1IC. Treatment with Taxol increased the amounts of nuclear - and ß_II-tubulin in K562 and HeLa cells and promoted the C promoter-binding factor 1–dependent transactivation activity of N1IC. We also show that nuclear ß_II-tubulin was bound on the C promoter-binding factor 1 response elements via the association with N1IC. These results suggest that nuclear ß_II-tubulin can modulate Notch signaling through interaction with N1IC in cancer cells.

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