Endoplasmic reticulum stress prolongs GH-induced Janus kinase (JAK2)/signal transducer and activator of transcription (STAT5), signaling pathway

Flores-Morales, A; Fernandez, L; Rico-Bautista, E; Umana, A; Negrin, C; Zhang, JG; Norstedt, G

Author(s): Flores-Morales, A; Fernandez, L; Rico-Bautista, E; Umana, A; Negrin, C; Zhang, JG; Norstedt, G;
Details: Publication Year 2001-09,Volume 15,Issue #9,Page 1471-1483
Journal Title: MOLECULAR ENDOCRINOLOGY
Publication Type: Journal Article
Abstract: The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway plays a crucial role in GH regulation of hepatic genes. Previous studies have demonstrated that the inactivation of the GH-induced JAK2/STAT5 pathway is regulated by protein translation and suppressors of cytokine signaling (SOCS). In this study we sought to explore the relationships between endoplasmic reticulum stress, GH-induced JAK2/STAT5 activity and SOCS expression, 1,2-bis(o-Aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl)ester (BAPTA-AM), used to provoke endoplasmic reticulum stress, caused a drastic inhibition of protein translation that correlated with the phosphorylation of the eukaryotic translation initiation factor 2 alpha. Both GH and BAPTA-AM caused a rapid induction of the transcription factor C/EBP homology protein (CHOP) and an additive effect was observed with combined treatment, which suggests a regulatory role of GH on endoplasmic reticulum stress. Endoplasmic reticulum stress did not interfere with the rapid GH activation of STAT5 DNA binding activity. However, BAPTA-AM prolonged the DNA binding activity of STAT5 without affecting STAT5 or JAK2 protein levels. GH-induced phosphorylation of JAK2 and STAT5 DNA binding activity were prolonged in the presence of BAPTA-AM, suggesting that endoplasmic reticulum stress prevents the inactivation of STAT5 DNA binding activity by modulating the rate of JAK2/STAT5 dephosphorylation. Like BAPTA-AM, the endoplasmic reticulum stressors dithiothreitol and A23187 also prolonged the GH-induced STAT5 DNA binding activity. We were not able to correlate BAPTA-AM effects to the GH-dependent expression of SOCS proteins or SOCS mRNA, suggesting that endoplasmic reticulum stress modulates the rate of JAK2/STAT5 dephosphorylation through mechanisms other than inhibition of SOCS expression. This study indicates that cellular stress may modulate transcription through the JAK/STAT pathway.
Publisher: ENDOCRINE SOC
Keywords: GROWTH-HORMONE RECEPTOR; RNA-POLYMERASE-II; PROTEIN-KINASE; GENE-TRANSCRIPTION; DOWN-REGULATION; INHIBITION; PHOSPHORYLATION; FAMILY; CHOP; COORDINATION
Publisher's Version: https://doi.org/10.1210/me.15.9.1471
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2001-09-01 12:00:00