Protection from β-cell apoptosis by inhibition of TGF-β/Smad3 signaling
| Autor: | Sushrut M. Pathy, Jose Manuel Mellado-Gil, Young Jae Bahn, Ying E. Zhang, Sushil G. Rane, Ji-Hyeon Lee |
|---|---|
| Přispěvatelé: | [Lee,JH, Mellado-Gil,JM, Bahn,YJ, Pathy,SM, Rane,SG] Cell Growth and Metabolism Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. [Zhang,YE] Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. [Mellado-Gil,JM] Biomedical Research and Innovation Institute of Cádiz (INiBiCA) Research Unit, Jerez University Hospital, Cádiz, Spain., This work was supported by funds from the NIH intramural program. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
FOXO1 Apoptosis Neogenesis Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] Mice 0302 clinical medicine Organisms::Eukaryota::Animals [Medical Subject Headings] 0303 health sciences B-Lymphocytes Rol biology lcsh:Cytology Chemistry Diabetes Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings] Type 2 diabetes β-cell Phosphorylation Signal transduction Signal Transduction Intolerancia a la glucosa Immunology Factor de crecimiento transformador beta 030209 endocrinology & metabolism Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models Animal::Disease Models Animal [Medical Subject Headings] Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Intercellular Signaling Peptides and Proteins::Transforming Growth Factors::Transforming Growth Factor beta::Transforming Growth Factor beta1 [Medical Subject Headings] Article Transforming Growth Factor beta1 03 medical and health sciences Cellular and Molecular Neuroscience Insulin resistance Células secretoras de insulina medicine Animals Humans Smad3 Protein lcsh:QH573-671 Autocrine signalling Glucose intolerance Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings] Transcription factor Pancreas Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::DNA-Binding Proteins::Smad Proteins::Smad Proteins Receptor-Regulated::Smad3 Protein [Medical Subject Headings] 030304 developmental biology Cell Proliferation Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] Role Cell Biology biology.organism_classification medicine.disease Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings] Disease Models Animal Glucose Glucosa Cancer research Proteína smad3 |
| Zdroj: | Cell Death and Disease, Vol 11, Iss 3, Pp 1-15 (2020) Cell Death & Disease |
| Popis: | Prevailing insulin resistance and the resultant hyperglycemia elicits a compensatory response from pancreatic islet beta cells (β-cells) that involves increases in β-cell function and β-cell mass. However, the sustained metabolic stress eventually leads to β-cell failure characterized by severe β-cell dysfunction and progressive loss of β-cell mass. Whereas, β-cell dysfunction is relatively well understood at the mechanistic level, the avenues leading to loss of β-cell mass are less clear with reduced proliferation, dedifferentiation, and apoptosis all potential mechanisms. Butler and colleagues documented increased β-cell apoptosis in pancreas from lean and obese human Type 2 diabetes (T2D) subjects, with no changes in rates of β-cell replication or neogenesis, strongly suggesting a role for apoptosis in β-cell failure. Here, we describe a permissive role for TGF-β/Smad3 in β-cell apoptosis. Human islets undergoing β-cell apoptosis release increased levels of TGF-β1 ligand and phosphorylation levels of TGF-β’s chief transcription factor, Smad3, are increased in human T2D islets suggestive of an autocrine role for TGF-β/Smad3 signaling in β-cell apoptosis. Smad3 phosphorylation is similarly increased in diabetic mouse islets undergoing β-cell apoptosis. In mice, β-cell-specific activation of Smad3 promotes apoptosis and loss of β-cell mass in association with β-cell dysfunction, glucose intolerance, and diabetes. In contrast, inactive Smad3 protects from apoptosis and preserves β-cell mass while improving β-cell function and glucose tolerance. At the molecular level, Smad3 associates with Foxo1 to propagate TGF-β-dependent β-cell apoptosis. Indeed, genetic or pharmacologic inhibition of TGF-β/Smad3 signals or knocking down Foxo1 protects from β-cell apoptosis. These findings reveal the importance of TGF-β/Smad3 in promoting β-cell apoptosis and demonstrate the therapeutic potential of TGF-β/Smad3 antagonism to restore β-cell mass lost in diabetes. |
| Databáze: | OpenAIRE |
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