XBP-1, a key regulator of unfolded protein response, activates transcription of IGF1 and Akt phosphorylation in zebrafish embryonic cell line

• Published in: Biochemical and biophysical research communications 2007-08, Vol.359 (3), p.778-783
• Main Authors: Hu, Meng-Chuen, Gong, Hong-Yi, Lin, Gen-Hwa, Hu, Shao-Yang, Chen, Mark Hung-Chih, Huang, Shin-Jie, Liao, Ching-Fong, Wu, Jen-Leih
• Format: Article
• Language: English
• Subjects: Akt; Amino Acid Sequence; Animals; Anti-apoptosis; Cell Line; Cloning, Molecular; Danio rerio; DNA, Complementary - genetics; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endoplasmic Reticulum - metabolism; ER stress; Freshwater; Humans; IGF1; Insulin-Like Growth Factor I - genetics; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Phosphorylation; Protein Folding; Proto-Oncogene Proteins c-akt - metabolism; Regulatory Factor X Transcription Factors; RNA, Messenger - genetics; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction; Time Factors; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - genetics; Unfolded protein response; Up-Regulation; X-Box Binding Protein 1; XBP-1; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.05.183

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.