Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 15, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI157086
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Funding
- NIDDK
- NIH [P30 DK020541, R01 DK116873, R01 DK116904, R01 DK125285, R01 DK105015, R01 DK129196, DK K01 128378, R01 GM132129, R35 CA232128, P01 CA203655]
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Resistance to regeneration of insulin-producing pancreatic β cells is a challenge in diabetes. Small molecule inhibitors of DYRK1A kinase have been found to induce proliferation of adult human β cells, but their mechanism of action is not fully understood. Through analysis of transcriptomic databases, researchers identified the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, inducing and maintaining cellular quiescence.
Resistance to regeneration of insulin-producing pancreatic ?? 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 ?? cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and ?? cell transcriptomic databases seeking to understand why ?? cells in insulinomas proliferate, while normal ?? cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human ?? 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 ?? cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.
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