KEIO RESEARCHERS INFORMATION SYSTEM

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Structural biochemistry

Research Keywords 【 Display / hide 】

Research Keywords 【 Display / hide 】

• NMR

• 転写因子

Papers 【 Display / hide 】

Papers 【 Display / hide 】

• 14-3-3ζ interacts with DNA-binding domain of FOXO3a and competitively dissociates DNA by dual-motif tethering

  Enomoto S., Kuwayama T., Nakatsuka S., Yokogawa M., Kawatsu K., Nakamura R., Kimura T., Tanabe M., Senda T., Saito J., Saya H., Osawa M.

  Nature Communications 17 ( 1503 )  2026.02

  Research paper (scientific journal), Lead author, Accepted,  ISSN  2041-1723

  　View Summary

  In cancer cells, Ras protein mutations activate a signaling cascade that phosphorylates kinases, transcription, and translation factors, driving cancer cell proliferation. One such factor, FOXO3a, promotes apoptosis-related gene transcription. However, in many cancer cells, FOXO3a is phosphorylated and is bound to 14-3-3ζ at phosphorylation sites. The 14-3-3ζ binding displaces phosphorylated FOXO3a from DNA, suppressing apoptosis. Since the phosphorylation sites are far from the DNA-binding domain (DBD) of FOXO3a, the mechanism of displacement remains unclear. Using isothermal titration calorimetry and fluorescence-detection size-exclusion chromatography, we find that 14-3-3ζ strongly displaces DNA from di-phosphorylated FOXO3a (dpFOXO3a), despite similar dissociation constants for dpFOXO3a–14-3-3ζ and dpFOXO3a–DNA. Nuclear magnetic resonance data identify weak, but direct binding of 14-3-3ζ to the DBD, suggesting direct competition. These findings suggest that 14-3-3ζ enhances its competitive ability by dual tethering to the DBD of FOXO3a via phosphorylation sites, effectively displacing DNA.

  • Access to Document (DOI)

• NMR 1H, 13C, 15N backbone resonance assignments of 14-3-3ζ binding region of human FOXO3a (residues 1-284)

  Enomoto S., Nakatsuka S., Kuwayama T., Kawatsu K., Yokogawa M., Osawa M.

  Biomolecular NMR Assignments 18 ( 2 ) 275 - 283 2024.12

  Research paper (scientific journal), Lead author, Accepted,  ISSN  18742718

  　View Summary

  In tumors, mutation in Ras proteins stimulates a signaling cascade through phosphorylation. Downstream of the cascade, many transcription and translation factors are up- or down-regulated by phosphorylation, leading to cancer progression. This phosphorylation cascade is sustained by 14-3-3ζ protein. 14-3-3ζ binds to its client proteins that are Ser/Thr-phosphorylated and prevents their dephosphorylation. One of those transcription factors is FOXO3a, whose transcriptional activity is suppressed in the phosphorylation cascade. FOXO3a binds to specific DNA sequences and activates the transcription of apoptosis-related proteins. In cancer cells, however, FOXO3a is phosphorylated, bound to 14-3-3ζ, and dissociated from the DNA, resulting in FOXO3a inactivation. To elucidate the mechanism of FOXO3a inactivation by the 14-3-3ζ binding, we aim to perform NMR analysis of the interaction between 14-3-3ζ and di-phosphorylated FOXO3a residues 1-284 (dpFOXO3a). Here, we report the backbone resonance assignments of dpFOXO3a, which are transferred from those of the N-terminal domain (NTD) and the DNA-binding domain (DBD) of dpFOXO3a.

  • Access to Document (DOI)

Presentations 【 Display / hide 】

Presentations 【 Display / hide 】

• 14-3-3ζ interacts with DNA-binding domain of FOXO3a and competitively dissociates DNA by dual-motif tethering

  Shota Enomoto, Tomoya Kuwayama, Shoichi Nakatsuka, Mariko Yokogawa, Kosaku Kawatsu, Risa Nakamura, Tomomi Kimura, Mikio Tanabe, Toshiya Senda, Jun Saito, Hideyuki Saya, Masanori Osawa

  [Domestic presentation]  第64回NMR討論会, 

  2025.11

  , 

  Poster presentation

• 14-3-3ζ Interacts with FOXO3a-DBD and Competitively Dissociates DNA through the Tethering Effects via Two Binding Motifs

  Shota Enomoto, Tomoya Kuwayama, Shoichi Nakatsuka, Mariko Yokogawa, Kosaku Kawatsu, Risa Nakamura, Mikio Tanabe, Toshiya Senda, Jun Saito, Hideyuki Saya, Masanori Osawa

  [International presentation]  The 30th International Conference on Magnetic Resonance in Biological Systems (ICMRBS 2024), 

  2024.08

  , 

  Poster presentation