| Autor: |
Charbord J; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Ren L; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Sharma RB; Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA., Johansson A; Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Ågren R; Department of Biology and Biological Engineering, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, Göteborg, Sweden., Chu L; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Tworus D; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Schulz N; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Charbord P; Sorbonne Université, Institut de Biologie Paris-Seine, CNRS UMR 7622, Inserm, Paris, France., Stewart AF; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Wang P; Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Alonso LC; Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA., Andersson O; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. olov.andersson@ki.se. |
| Abstrakt: |
It is known that β cell proliferation expands the β cell mass during development and under certain hyperglycemic conditions in the adult, a process that may be used for β cell regeneration in diabetes. Here, through a new high-throughput screen using a luminescence ubiquitination-based cell cycle indicator (LUCCI) in zebrafish, we identify HG-9-91-01 as a driver of proliferation and confirm this effect in mouse and human β cells. HG-9-91-01 is an inhibitor of salt-inducible kinases (SIKs), and overexpression of Sik1 specifically in β cells blocks the effect of HG-9-91-01 on β cell proliferation. Single-cell transcriptomic analyses of mouse β cells demonstrate that HG-9-91-01 induces a wave of activating transcription factor (ATF)6-dependent unfolded protein response (UPR) before cell cycle entry. Importantly, the UPR wave is not associated with an increase in insulin expression. Additional mechanistic studies indicate that HG-9-91-01 induces multiple signalling effectors downstream of SIK inhibition, including CRTC1, CRTC2, ATF6, IRE1 and mTOR, which integrate to collectively drive β cell proliferation. |
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