دورية أكاديمية
TBK1 regulates regeneration of pancreatic β-cells.
العنوان: | TBK1 regulates regeneration of pancreatic β-cells. |
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المؤلفون: | Jia YF; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA., Jeeva S; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA., Xu J; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA., Heppelmann CJ; Proteomics Research Center, Mayo Clinic, Rochester, MN, 55905, USA., Jang JS; Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA., Slama MQ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA., Tapadar S; School of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA., Oyelere AK; School of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA., Kang SM; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA., Matveyenko AV; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA.; Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Peterson QP; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, 55905, USA.; Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Shin CH; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA. cshin@gsu.edu.; Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA. cshin@gsu.edu. |
المصدر: | Scientific reports [Sci Rep] 2020 Nov 09; Vol. 10 (1), pp. 19374. Date of Electronic Publication: 2020 Nov 09. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: London : Nature Publishing Group, copyright 2011- |
مواضيع طبية MeSH: | Cell Proliferation* , Gene Expression Regulation, Enzymologic* , Regeneration*, Insulin-Secreting Cells/*enzymology , Protein Serine-Threonine Kinases/*biosynthesis, Animals ; Cell Line, Tumor ; Gene Silencing ; Human Embryonic Stem Cells/enzymology ; Humans ; Insulin/genetics ; Insulin/metabolism ; Insulin Secretion ; Protein Serine-Threonine Kinases/genetics ; Rats |
مستخلص: | Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells. |
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معلومات مُعتمدة: | R01 AI093772 United States AI NIAID NIH HHS; R01DK098468 United States NH NIH HHS; R56DK111630 United States NH NIH HHS; R01AI093772 United States NH NIH HHS; R01 DK098468 United States DK NIDDK NIH HHS; R56 DK111630 United States DK NIDDK NIH HHS |
المشرفين على المادة: | 0 (Insulin) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.11.1 (TBK1 protein, human) |
تواريخ الأحداث: | Date Created: 20201110 Date Completed: 20210311 Latest Revision: 20211204 |
رمز التحديث: | 20240628 |
مُعرف محوري في PubMed: | PMC7653919 |
DOI: | 10.1038/s41598-020-76600-6 |
PMID: | 33168920 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2045-2322 |
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DOI: | 10.1038/s41598-020-76600-6 |