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

14 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

Fingerprint

Zinc
Down-Regulation
Phosphatidylinositol 3-Kinases
Notch Receptors
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Protein Stability
Transcription
Modulation
Proteins
wortmannin

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway. / Baek, Sang Hyun; Kim, Mi Yeon; Mo, Jung Soon; Ann, Eun Jung; Lee, Kyu Shik; Park, Ji Hye; Kim, Jin Young; Seo, Mi Sun; Choi, Eui Ju; Park, Hee Sae.

In: Cancer Letters, Vol. 255, No. 1, 18.09.2007, p. 117-126.

Research output: Contribution to journalArticle

Baek, Sang Hyun ; Kim, Mi Yeon ; Mo, Jung Soon ; Ann, Eun Jung ; Lee, Kyu Shik ; Park, Ji Hye ; Kim, Jin Young ; Seo, Mi Sun ; Choi, Eui Ju ; Park, Hee Sae. / Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway. In: Cancer Letters. 2007 ; Vol. 255, No. 1. pp. 117-126.
@article{3e6975c3f90c4522ad827c0ba1133de2,
title = "Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway",
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.",
keywords = "Akt, Cytoplasmic retention, LY294002, Notch intracellular domain, Phosphatidylinositol 3-kinase, RBP-Jk, Wortmannin, Zinc",
author = "Baek, {Sang Hyun} and Kim, {Mi Yeon} and Mo, {Jung Soon} and Ann, {Eun Jung} and Lee, {Kyu Shik} and Park, {Ji Hye} and Kim, {Jin Young} and Seo, {Mi Sun} and Choi, {Eui Ju} and Park, {Hee Sae}",
year = "2007",
month = "9",
day = "18",
doi = "10.1016/j.canlet.2007.04.002",
language = "English",
volume = "255",
pages = "117--126",
journal = "The BMJ",
issn = "0730-6512",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway

AU - Baek, Sang Hyun

AU - Kim, Mi Yeon

AU - Mo, Jung Soon

AU - Ann, Eun Jung

AU - Lee, Kyu Shik

AU - Park, Ji Hye

AU - Kim, Jin Young

AU - Seo, Mi Sun

AU - Choi, Eui Ju

AU - Park, Hee Sae

PY - 2007/9/18

Y1 - 2007/9/18

N2 - 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.

AB - 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.

KW - Akt

KW - Cytoplasmic retention

KW - LY294002

KW - Notch intracellular domain

KW - Phosphatidylinositol 3-kinase

KW - RBP-Jk

KW - Wortmannin

KW - Zinc

UR - http://www.scopus.com/inward/record.url?scp=34547652560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34547652560&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2007.04.002

DO - 10.1016/j.canlet.2007.04.002

M3 - Article

VL - 255

SP - 117

EP - 126

JO - The BMJ

JF - The BMJ

SN - 0730-6512

IS - 1

ER -