Zinc-induced downregulation of Notch signaling is associated with cytoplasmic retention of Notch1-IC and RBP-Jk via PI3k-Akt signaling pathway.
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 (DeltaEN1) 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.
Baek
Sang-Hyun
SH
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, 300, Yongbong-Dong, Buk-Ku, Gwangju, Republic of Korea.
Kim
Mi-Yeon
MY
Mo
Jung-Soon
JS
Ann
Eun-Jung
EJ
Lee
Kyu Shik
KS
Park
Ji-Hye
JH
Kim
Jin-Young
JY
Seo
Mi-Sun
MS
Choi
Eui-Ju
EJ
Park
Hee-Sae
HS
D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000096:biosynthesis*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D015398:Signal Transduction; D000077191:Wortmannin; D015032:Zinc / Q000494:pharmacology*
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009025:Morpholines; C497570:RBPJ protein, human; D051881:Receptor, Notch1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015032:Zinc; D000077191:Wortmannin