GSE200477: Polysome profiling quantified by RNA sequencing in PANC1 cells treated with MNK2 inhibitors or DMSO

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GROUP CONDITION SAMPLES
pancreatic ductal adenocarcinoma
GSM6034822 GSM6034823 GSM6034824 GSM6034825 GSM6034826 GSM6034827 GSM6034828 GSM6034829
GSM6034806 GSM6034807 GSM6034808 GSM6034809 GSM6034810 GSM6034811 GSM6034812 GSM6034813
GSM6034814 GSM6034815 GSM6034816 GSM6034817 GSM6034818 GSM6034819 GSM6034820 GSM6034821
Description

Submission Date: Apr 08, 2022

Summary: Regenerating pancreatic b-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of b-cell regeneration but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction that was genetically validated in vivo. CID661578 increased b-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding EIF4G in the translation initiation complex at the mRNA cap. This blocking activity augmented the interaction between EIF4E and EIF4G, which is necessary for both hypertranslation and b-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in b-cell regeneration, a role that warrants further investigation in diabetes.

GEO Accession ID: GSE200477

PMID: 35697798

Description

Submission Date: Apr 08, 2022

Summary: Regenerating pancreatic b-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of b-cell regeneration but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction that was genetically validated in vivo. CID661578 increased b-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids. Mechanistically, we found that CID661578 boosts protein synthesis and regeneration by blocking MNK2 from binding EIF4G in the translation initiation complex at the mRNA cap. This blocking activity augmented the interaction between EIF4E and EIF4G, which is necessary for both hypertranslation and b-cell regeneration. Taken together, our findings demonstrate a targetable role of MNK2-controlled translation in b-cell regeneration, a role that warrants further investigation in diabetes.

GEO Accession ID: GSE200477

PMID: 35697798

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