Disrupting the DREAM complex enables proliferation of adult human pancreatic β cells

被引：22

作者：

Wang, Peng ^{[1
,2
]}

Karakose, Esra ^{[1
,2
]}

Argmann, Carmen ^{[3
]}

Wang, Huan ^{[4
]}

Balev, Metodi ^{[2
]}

Brody, Rachel, I ^{[5
]}

Rivas, Hembly G. ^{[6
,7
]}

Liu, Xinyue ^{[6
]}

Wood, Olivia ^{[1
,2
]}

Liu, Hongtao ^{[1
,2
]}

Choleva, Lauryn ^{[1
,8
]}

Hasson, Dan ^{[9
,10
,11
]}

Bernstein, Emily ^{[9
,10
,12
]}

Paulo, Joao A. ^{[6
]}

Scott, Donald K. ^{[1
,2
]}

Lambertini, Luca ^{[1
,2
]}

DeCaprio, James A. ^{[6
,7
]}

Stewart, Andrew F. ^{[1
,2
]}

机构：

[1] Icahn Sch Med Mt Sinai, Diabet Obes Metab Inst, Atran 5,POB 1152,One Gustave Levy Pl, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[4] Sema4, Stamford, CT USA

[5] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA

[6] Dana Farber Canc Inst, Boston, MA 02115 USA

[7] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[8] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Bioinformat Next Generat Sequencing BiNGS Shared, New York, NY 10029 USA

[12] Icahn Sch Med Mt Sinai, Grad Sch Biomed Sci, New York, NY 10029 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2022年 / 132卷 / 15期

关键词：

DECOY SEARCH STRATEGY; PROTEIN-PHOSPHORYLATION; TRANSCRIPTION FACTOR; CYCLE; EXPRESSION; APOPTOSIS; GROWTH; FOXM1; MASS; REGENERATION;

D O I：

10.1172/JCI157086

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页数：15

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