CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced β-Cell Apoptosis
| Autor: | Jacqueline F. Rivera, Safia Costes, Jonathan D. Hoang, Alexandra E. Butler, Tatyana Gurlo, Megan Cory, Peter C. Butler |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Aging Apoptosis CHOP Inbred C57BL Medical and Health Sciences Mice 0302 clinical medicine Endocrinology hemic and lymphatic diseases Insulin-Secreting Cells 2.1 Biological and endogenous factors Aetiology Original Research Mice Knockout geography.geographical_feature_category Diabetes General Medicine Biological Sciences Endoplasmic Reticulum Stress Islet Islet Amyloid Polypeptide Signal transduction Type 2 Signal Transduction endocrine system medicine.medical_specialty Knockout Biology Endocrinology & Metabolism 03 medical and health sciences Internal medicine Diabetes Mellitus medicine Animals Humans Molecular Biology Metabolic and endocrine geography Agricultural and Veterinary Sciences Endoplasmic reticulum Autophagy ATF4 Mice Inbred C57BL 030104 developmental biology Diabetes Mellitus Type 2 Unfolded protein response Cancer research Transcription Factor CHOP 030217 neurology & neurosurgery |
| Zdroj: | Molecular endocrinology (Baltimore, Md.), vol 30, iss 4 |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | The islet in type 2 diabetes is characterized by β-cell loss, increased β-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce β-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and β-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP−/− mice, with relatively preserved β-cell mass and decreased β-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy/lysosomal pathway in β-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced β-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated. |
| Databáze: | OpenAIRE |
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