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

The desensitization of the GH-induced Janus kinase 2 (JAK2) and signal tran sducer and activator of transcription 5 (STAT5) signaling pathway plays a c rucial role in GH regulation of hepatic genes. Previous studies have demons trated that the inactivation of the GH-induced JAK2/STAT5 pathway is regula ted by protein translation and suppressors of cytokine signaling (SOCS). In this study we sought to explore the relationships between endoplasmic reti culum stress, GH-induced JAK2/STAT5 activity and SOCS expression, 1,2-bis(o -Aminophenoxy)ethane-N,N,N,N-tetraacetic acid (acetoxymethyl)ester (BAPTA-A M), used to provoke endoplasmic reticulum stress, caused a drastic inhibiti on of protein translation that correlated with the phosphorylation of the e ukaryotic translation initiation factor 2 alpha. Both GH and BAPTA-AM cause d a rapid induction of the transcription factor C/EBP homology protein (CHO P) and an additive effect was observed with combined treatment, which sugge sts a regulatory role of GH on endoplasmic reticulum stress. Endoplasmic re ticulum stress did not interfere with the rapid GH activation of STAT5 DNA binding activity. However, BAPTA-AM prolonged the DNA binding activity of S TAT5 without affecting STAT5 or JAK2 protein levels. GH-induced phosphoryla tion of JAK2 and STAT5 DNA binding activity were prolonged in the presence of BAPTA-AM, suggesting that endoplasmic reticulum stress prevents the inac tivation of STAT5 DNA binding activity by modulating the rate of JAK2/STAT5 dephosphorylation. Like BAPTA-AM, the endoplasmic reticulum stressors dith iothreitol and A23187 also prolonged the GH-induced STAT5 DNA binding activ ity. We were not able to correlate BAPTA-AM effects to the GH-dependent exp ression of SOCS proteins or SOCS mRNA, suggesting that endoplasmic reticulu m stress modulates the rate of JAK2/STAT5 dephosphorylation through mechani sms other than inhibition of SOCS expression. This study indicates that cel lular stress may modulate transcription through the JAK/STAT pathway.