Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells.
Adolescent
Adult
Aged
Animals
Cell Line
Cell Proliferation
Diabetes Mellitus, Type 2
/ drug therapy
Female
Harmine
/ pharmacology
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Humans
Insulin-Secreting Cells
/ drug effects
Male
Mice
Mice, Inbred C57BL
Middle Aged
Monoamine Oxidase Inhibitors
/ pharmacology
Myeloid-Lymphoid Leukemia Protein
/ antagonists & inhibitors
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Protein-Tyrosine Kinases
/ antagonists & inhibitors
Smad Proteins
/ antagonists & inhibitors
Stem Cells
Transforming Growth Factor beta
/ antagonists & inhibitors
Young Adult
Dyrk Kinases
DYRK1A
SMAD
TGFbeta
beta cell
diabetes
harmine
proliferation
regeneration
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
05 03 2019
05 03 2019
Historique:
received:
20
03
2018
revised:
03
08
2018
accepted:
30
11
2018
pmc-release:
05
03
2020
pubmed:
26
12
2018
medline:
12
5
2020
entrez:
25
12
2018
Statut:
ppublish
Résumé
Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFβSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers. This synergy reflects activation of cyclins and cdks by DYRK1A inhibition, accompanied by simultaneous reductions in key cell-cycle inhibitors (CDKN1C and CDKN1A). The latter results from interference with the basal Trithorax- and SMAD-mediated transactivation of CDKN1C and CDKN1A. Notably, combined DYRK1A and TGFβ inhibition allows preservation of beta cell differentiated function. These beneficial effects extend from normal human beta cells and stem cell-derived human beta cells to those from people with type 2 diabetes, and occur both in vitro and in vivo.
Identifiants
pubmed: 30581122
pii: S1550-4131(18)30742-3
doi: 10.1016/j.cmet.2018.12.005
pmc: PMC6402958
mid: NIHMS1516423
pii:
doi:
Substances chimiques
KMT2A protein, human
0
Monoamine Oxidase Inhibitors
0
Smad Proteins
0
Transforming Growth Factor beta
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Harmine
4FHH5G48T7
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Protein-Tyrosine Kinases
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
638-652.e5Subventions
Organisme : NIDDK NIH HHS
ID : UC4 DK104211
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116873
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK098085
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108905
Pays : United States
Organisme : NIDDK NIH HHS
ID : P60 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105015
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020541
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020593
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.
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