CHOP Deficiency Ameliorates ERK5 Inhibition-Mediated Exacerbation of Streptozotocin-Induced Hyperglycemia and Pancreatic beta-Cell Apoptosis
Dae-Hwan Nam1,2, Jung-Hwa Han1, Jae Hyang Lim3, Kwon Moo Park4, and Chang-Hoon Woo1,*
1Department of Pharmacology and Smart-aging Convergence Research Center, Yeungnam University College of Medicine,
Daegu 42415, Korea, 2Predictive Model Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical
Technology, Daejeon 34114, Korea, 3Department of Microbiology, Ewha Womans University School of Medicine, Seoul 03760,
Korea, 4Department of Anatomy, Kyungpook National University School of Medicine, Daegu 41566, Korea
*Correspondence: changhoon_woo@yu.ac.kr
Received September 12, 2017; Revised May 14, 2017; Accepted June 6, 2017.; Published online July 6, 2017.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-sa/3.0/).
ABSTRACT
Streptozotocin (STZ)-induced murine models of type 1 diabetes have been used to examine ER stress during pancreatic beta- cell apoptosis, as this ER stress plays important roles in the pathogenesis and development of the disease. However, the mechanisms linking type 1 diabetes and the ER stressmodulating anti-diabetic signaling pathway remain to be addressed, though it was recently established that ERK5 (Extracellular- signal-regulated kinase 5) contributes to the pathogeneses of diabetic complications. This study was undertaken to explore the mechanism whereby ERK5 inhibition instigates pancreatic beta-cell apoptosis via an ER stress-dependent signaling pathway. STZ-induced diabetic WT and CHOP deficient mice were i.p. injected every 2 days for 6 days under BIX02189 (a specific ERK5 inhibitor) treatment in order to evaluate the role of ERK5. Hyperglycemia was exacerbated by co-treating C57BL/6J mice with STZ and BIX02189 as compared with mice administered STZ alone. In addition, immunoblotting data revealed that ERK5 inhibition activated the unfolded protein response pathway accompanying apoptotic events, such as, PARP-1 and caspase-3 cleavage. Interestingly, ERK5 inhibition-induced exacerbation of pancreatic beta-cell apoptosis was inhibited in CHOP deficient mice. Moreover, transduction of adenovirus encoding an active mutant form of MEK5alpha, an upstream kinase of ERK5, inhibited STZinduced unfolded protein responses and beta-cell apoptosis. These results suggest that ERK5 protects against STZ-induced pancreatic beta-cell apoptosis and hyperglycemia by interrupting the ER stress-mediated apoptotic pathway.
Keywords: apoptosis, beta-cell, CHOP, ER stress, ERK5


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