PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28.

The interaction between proteins and RNA is crucial for regulating gene expression, with dysregulation often linked to diseases such as cancer. The RNA-binding protein (RBP) Lin28 inhibits the tumor suppressor microRNA (miRNA) let-7, making it a significant oncogenic factor in tumor progression and metastasis. In this study, a small molecule is used that binds Lin28 and blocks its inhibition of let-7.

Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia.

Diabetogenic ablation of beta cells in mice triggers a regenerative response whereby surviving beta cells proliferate and euglycemia is regained. Here, we identify and characterize heterogeneity in response to beta cell ablation. Efficient beta cell elimination leading to severe hyperglycemia (>28 mmol/L), causes permanent diabetes with failed regeneration despite cell cycle engagement of surviving beta cells.

Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.

β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53.