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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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

摘要

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.