Disrupting the DREAM complex enables proliferation of adult human pancreatic ß cells.
J Clin Invest
; 132(15)2022 08 01.
Article
in En
| MEDLINE
| ID: mdl-35700053
ABSTRACT
Resistance to regeneration of insulin-producing pancreatic ß 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 ß cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and ß cell transcriptomic databases seeking to understand why ß cells in insulinomas proliferate, while normal ß cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human ß 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 ß cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pancreatic Neoplasms
/
Diabetes Mellitus, Type 2
/
Insulin-Secreting Cells
/
Insulinoma
Limits:
Adult
/
Humans
Language:
En
Journal:
J Clin Invest
Year:
2022
Document type:
Article