XBP-1, a Key Regulator of Unfolded Protein Response, Activates Transcription of IGF1 and Akt Phosphorylation in Zebrafish Embryonic Cell Line

Biochem Biophys Res Commun. 2007 Aug 3;359(3):778-83. doi: 10.1016/j.bbrc.2007.05.183. Epub 2007 Jun 4.

Abstract

The unfolded protein response (UPR) is a conserved and adaptive cellular response to increase cell survival during ER stress. XBP-1 spliced form (XBP-1S) generated by IRE1 endoribonuclease is a key transcriptional regulator in UPR to activate genes involved in protein folding and degradation to restore ER function. Although Akt activation was suggested to be a pro-survival pathway activated during ER stress, the signal to trigger Akt is still not clear. In this study, we report IGF1 transcription and Akt phosphorylation are enhanced in XBP-1S stably overexpressed clone of zebrafish embryonic cell line (ZF4). In addition, zebrafish IGF1 intron1 with predicted UPRE (XBP-1S binding sites) and ERSE (ATF6/XBP-1S binding site) linked with basal promoter could be activated by XBP-1S, not by XBP-1 unspliced form (XBP-1U). Furthermore, we demonstrate that expression of endogenous IGF1 is transiently induced as XBP-1 splicing during ER stress in parallel to ER chaperone GRP78/Hspa5 and ER resided E3 ubiquitin ligase Synoviolin in ZF4 cells by quantitative PCR. Our results suggest zebrafish XBP-1S not only activates genes responsible for protein folding, transporting, glycosylation and ER associated degradation but also activates anti-apoptosis signal via IGF1/Akt pathway in unfolded protein response to cope with ER stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cloning, Molecular
  • DNA, Complementary / genetics
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Insulin-Like Growth Factor I / genetics*
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Protein Folding
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • Regulatory Factor X Transcription Factors
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Time Factors
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / genetics*
  • Up-Regulation
  • X-Box Binding Protein 1
  • Zebrafish / embryology
  • Zebrafish / genetics*
  • Zebrafish / metabolism*

Substances

  • DNA, Complementary
  • DNA-Binding Proteins
  • RNA, Messenger
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-akt

Associated data

  • GENBANK/AF420256