Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway

Sang Hyun Baek, Mi Yeon Kim, Jung Soon Mo, Eun Jung Ann, Kyu Shik Lee, Ji Hye Park, Jin Young Kim, Mi Sun Seo, Eui Ju Choi, Hee Sae Park

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The Notch signaling pathway appears to perform an important function in the determination of cell fate and in differentiation, in a wide variety of organisms and cell types. In this study, we provide evidence that the inactivation of Notch signaling by zinc is achieved via a PI3K-Akt-dependent, cytoplasmic retention of Notch1-IC and RBP-Jk. Extracellular zinc has been determined to inhibit constitutive active mutants of both Notch1 (ΔEN1) and Notch1-IC-mediated transcription. However, in such cases, neither the cleavage pattern of Notch nor the protein stability of Notch1-IC and RBP-Jk was found to have significantly changed. With regard to the modulation of Notch signaling, zinc appears to exert a significant negative influence on the binding occurring between Notch1 and RBP-Jk, both in vivo and in vitro. The zinc-induced inhibition of Notch signaling can be rescued via pretreatment with wortmannin or LY294002, both of which are specific PI3K signaling pathway inhibitors. Furthermore, we ascertained that zinc triggers the cytoplasmic retention of Notch1-IC and RBP-Jk, and that cytoplasmic retention could be rescued via treatment with wortmannin. Overall, we have determined that an important relationship exists between zinc and the Notch1 signaling pathway, and that this relationship is intimately involved with the cytoplasmic retention of Notch and RBP-Jk.

Original languageEnglish
Pages (from-to)117-126
Number of pages10
JournalCancer letters
Volume255
Issue number1
DOIs
Publication statusPublished - 2007 Sep 18

Keywords

  • Akt
  • Cytoplasmic retention
  • LY294002
  • Notch intracellular domain
  • Phosphatidylinositol 3-kinase
  • RBP-Jk
  • Wortmannin
  • Zinc

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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