Role of KSRP in post-transcriptional regulation of pancreatic beta cells

Abstract

Dysfunctions in pancreatic beta cells can lead to impairments in insulin production and secretion, cell death and, eventually, type 2 diabetes mellitus (DM2). The comprehension of the mechanisms that regulate synthesis of proteins involved in beta cell function and survival is essential to understand how such dysfunctions can take place or be prevented. KH-type splicing regulatory protein (KSRP) modulates gene expression throughout post-transcriptional regulation, participating in mechanisms such as alternative splicing, mRNA degradation and microRNAs primary processing and maturation. The phosphorylation by AKT may prevent KSRP from binding to specific mRNAs or from recruiting the mRNA degradation machinery, while concurrently it may enhance the interaction between KSRP and microRNAs maturation complexes. Although there are studies describing the role of KSRP in tissues intimately related to glycemic homeostasis, to date its effects have not been investigated in pancreatic beta cells, even though its expression has been reported. Since KSRP activity is regulated by important pathways for beta cell function and maintenance (such as PI3K/AKT and MAPK/ERK), we believe KSRP regulates the expression of key components involved in these processes. Thus, we aim to evaluate the role of KSRP in post-transcriptional regulation in pancreatic beta cells. To that end, we will develop KSRP knock-down and overexpressed models in INS-1E cells, followed by function and cellular viability analyses. Furthermore, microRNAs relevant to beta cells will be evaluated in these models. Thus, this project may contribute to the elucidation of essential mechanisms to the synthesis and regulation of beta cell proteins and, therefore, to the development of possible therapeutic strategies against DM2. (AU)