@article{22b5d2a0efaf4da1a0af334bfd2fb378,
title = "Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells",
abstract = "Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.",
author = "Peng Wang and Esra Karakose and Carmen Argmann and Huan Wang and Metodi Balev and Brody, {Rachel I.} and Rivas, {Hembly G.} and Xinyue Liu and Olivia Wood and Hongtao Liu and Lauryn Choleva and Dan Hasson and Emily Bernstein and Paulo, {Joao A.} and Scott, {Donald K.} and Luca Lambertini and DeCaprio, {James A.} and Stewart, {Andrew F.}",
note = "Funding Information: The authors wish to thank Bonnie and Joel Bergstein, Lonnie and Thomas Schwartz, and Martha and Fred Farkouh families for their constant support of this research. We also thank the NIDDK-supported Human Islet and Adenovirus Core (HIAC) of the Einstein-Sinai Diabetes Research Center (ES-DRC), and the NIDDK Integrated Islet Distribution Program (IIDP), Prodo Laboratories, Patrick MacDonald at the Alberta Diabetes Institute and Tatsuya Kin at the University of Alberta, Edmonton, Alberta, Canada, Piotr Witkowski at the University of Chicago, Chicago, Illinois, and Fouad Kandeel at the City of Hope Medical Center, Duarte, California, for providing human organ donor islets. We thank the Icahn School of Medicine Tissue Biorepository for providing deidentified samples of normal human pancreas. We also thank Mark Keller and Alan Attie at the University of Wisconsin for sharing adenoviruses expressing constitutively active mNFAT1 and mNFAT2. Finally, we thank Steven Gygi and the Taplin Mass Spectrometry facility at Harvard Medical School for use of their instrumentation. This work was supported by NIH grants P30 DK020541, R01 DK116873, R01 DK116904, R01 DK125285, R01 DK105015, R01 DK129196, DK K01 128378, R01 GM132129, R35 CA232128, and P01 CA203655. Publisher Copyright: {\textcopyright} 2022 American Society for Clinical Investigation. All rights reserved.",
year = "2022",
month = aug,
day = "1",
doi = "10.1172/JCI157086",
language = "English",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "15",
}