TBK1 regulates regeneration of pancreatic β-cells
Autor: | Carrie J. Heppelmann, Subhasish Tapadar, Adegboyega K. Oyelere, Jin Sung Jang, Quinn P. Peterson, Aleksey V. Matveyenko, Chong Hyun Shin, Yun Fang Jia, Jin Xu, Subbiah Jeeva, Michael Q. Slama, Sang-Moo Kang |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cell biology Human Embryonic Stem Cells Phosphodiesterase 3 lcsh:Medicine 030209 endocrinology & metabolism IκB kinase Protein Serine-Threonine Kinases Article Gene Expression Regulation Enzymologic Transcriptome 03 medical and health sciences 0302 clinical medicine TANK-binding kinase 1 Cell Line Tumor Insulin-Secreting Cells Insulin Secretion medicine Animals Humans Insulin Regeneration Gene silencing Gene Silencing lcsh:Science Cell Proliferation Multidisciplinary Cell growth Kinase Chemistry lcsh:R Streptozotocin Chemical biology Rats 030104 developmental biology lcsh:Q medicine.drug |
Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-13 (2020) Scientific Reports |
ISSN: | 2045-2322 |
Popis: | 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. |
Databáze: | OpenAIRE |
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