The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development.
Animals
Cell Proliferation
/ drug effects
Cyclin D1
/ genetics
Cyclin D2
/ genetics
Female
Glucose
/ pharmacology
Humans
Insulin
/ metabolism
Insulin-Secreting Cells
/ cytology
MAP Kinase Kinase Kinases
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 10
/ antagonists & inhibitors
Obesity
/ metabolism
Pancreas
/ growth & development
RNA Interference
RNA, Small Interfering
/ metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction
/ drug effects
Beta-cell mass
Mapk
Obesity
Postnatal development
Pregnancy
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
Jan 2021
Jan 2021
Historique:
received:
08
06
2019
accepted:
04
03
2020
pubmed:
20
3
2020
medline:
17
2
2021
entrez:
20
3
2020
Statut:
ppublish
Résumé
Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk, Jnk3, Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3, CCND1 and CCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.
Identifiants
pubmed: 32189007
doi: 10.1007/s00018-020-03499-7
pii: 10.1007/s00018-020-03499-7
doi:
Substances chimiques
Ccnd1 protein, rat
0
Ccnd2 protein, rat
0
Cyclin D2
0
Insulin
0
RNA, Small Interfering
0
Cyclin D1
136601-57-5
Mitogen-Activated Protein Kinase 10
EC 2.7.1.-
MAP Kinase Kinase Kinases
EC 2.7.11.25
mitogen-activated protein kinase kinase kinase 12
EC 2.7.11.25
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
287-298Subventions
Organisme : Agence Nationale de la Recherche
ID : ANR-10-LABEX-46
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