| Title : A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis - Xiao_2016_J.Biol.Chem_291_23224 |
| Author(s) : Xiao X , Jones G , Sevilla WA , Stolz DB , Magee KE , Haughney M , Mukherjee A , Wang Y , Lowe ME |
| Ref : Journal of Biological Chemistry , 291 :23224 , 2016 |
| Abstract : Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP. |
| ESTHER : Xiao_2016_J.Biol.Chem_291_23224 |
| PubMedSearch : Xiao_2016_J.Biol.Chem_291_23224 |
| PubMedID: 27650499 |
| Gene_locus related to this paper: human-CEL |
| Gene_locus related to this paper: human-CEL |
Xiao X, Jones G, Sevilla WA, Stolz DB, Magee KE, Haughney M, Mukherjee A, Wang Y, Lowe ME (2016)
A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis
Journal of Biological Chemistry
291 :23224
Xiao X, Jones G, Sevilla WA, Stolz DB, Magee KE, Haughney M, Mukherjee A, Wang Y, Lowe ME (2016)
Journal of Biological Chemistry
291 :23224