MCL-1 is a Key Anti-Apoptotic Protein in Human and Rodent Pancreatic Beta cells
| Autor: | Makiko Fukaya, Natalia Moretti Violato, Decio L. Eizirik, Violette Dirix, Alessandra K Cardozo, Lorella Marselli, Andreas Strasser, Nathalie Pachera, Kira Meyerovich, Piero Marchetti |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Myeloid Cell Leukemia Sequence 1 Protein -- genetics -- metabolism Endocrinology Diabetes and Metabolism Apoptosis Mice 0302 clinical medicine Endocrinology immune system diseases Insulin-Secreting Cells Cells Cultured Mice Knockout Cultured Kinase Sciences bio-médicales et agricoles 3. Good health Cell biology Endocrinologie Diabetes and Metabolism Médecine interne 030220 oncology & carcinogenesis Knockout mouse Cytokines RNA Interference medicine.drug medicine.medical_specialty Cells Knockout Biology Proinflammatory cytokine Diabetes Mellitus Experimental Inflammation -- metabolism 03 medical and health sciences Experimental Downregulation and upregulation Métabolisme Internal medicine medicine Diabetes Mellitus Internal Medicine Animals Humans Inflammation Cytokines -- genetics -- metabolism Diabétologie Endoplasmic reticulum Protein turnover Apoptosis -- physiology Streptozotocin 030104 developmental biology Insulin-Secreting Cells -- metabolism Myeloid Cell Leukemia Sequence 1 Protein |
| Zdroj: | Diabetes (New York, N.Y.), 66 (9 Diabetes |
| Popis: | Induction of endoplasmic reticulum stress and activation of the intrinsic apoptotic pathway is widely believed to contribute to β-cell death in type 1 diabetes (T1D). MCL-1 is an anti-apoptotic member of the BCL-2 protein family, whose depletion causes apoptosis in rodent β-cells in vitro. Importantly, decreased MCL-1 expression was observed in islets from T1D patients. We report here that MCL-1 downregulation is associated with cytokine-mediated killing of human β-cells, a process partially prevented by MCL-1 overexpression. By generating a β-cell specific Mcl-1 knockout mouse strain (βMcl-1KO), we observed that, surprisingly, MCL-1 ablation does not affect islet development and function. β-cells from βMcl-1KO mice were, however, more susceptible to cytokine-induced apoptosis. Moreover, βMcl-1KO mice displayed higher hyperglycaemia and lower pancreatic insulin content after multiple low dose streptozotocin treatment. We found that the kinase GSK3β, the E3 ligases MULE and βTrCP and the deubiquitinase USP9x, regulate cytokine-mediated MCL-1 protein turnover in rodent β-cells. Our results identify MCL-1 as a critical pro-survival protein for preventing β-cell death and clarify the mechanisms behind its downregulation by pro-inflammatory cytokines. Development of strategies to prevent MCL-1 loss in the early stages of T1D may enhance β-cell survival and thereby delay or prevent disease progression. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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