MIST1 regulates the pancreatic acinar cell expression of Atp2c2, the gene encoding secretory pathway calcium ATPase 2

Abstract

MIST1 is a transcription factor expressed in pancreatic acinar cells and other serous exocrine cells. Mice harboring a targeted deletion of the Mist1 gene (Mist1−/−) exhibit alterations in acinar regulated exocytosis and aberrant Ca2+ signaling that are normally controlled by acinar cell Ca2+-ATPases. Previous studies indicated that total sarcoendoplasmic reticulum Ca2+-ATPases (SERCA) and plasma membrane Ca2+-ATPases (PMCA) remained unaffected in Mist1−/− acinar cultures. Therefore, we have assessed the expression of Atp2c2, the gene that encodes the secretory pathway Ca2+-ATPase 2 (SPCA2). We revealed a dramatic decrease in pancreatic expression of Atp2a2 mRNA and SPCA2 protein in Mist1−/− mice. Surprisingly, this analysis indicated that the acinar-specific Atp2c2 mRNA is a novel transcript, consisting of only the 3′ end of the gene and the protein and localizes to the endoplasmic reticulum. Expression of SPCA2 was also lost in Mist1−/− secretory cells of the salivary glands and seminal vesicles, suggesting that Atp2c2 transcription is regulated by MIST1. Indeed, inducible MIST1 expression in Mist1−/− pancreatic acinar cells restored normal Atp2c2 expression, supporting a role for MIST1 in regulating the Atp2c2 gene. Based on these results, we have identified a new Atp2c2 transcript, the loss of which may be linked to the Mist1−/− phenotype.

Silencing of the Fibroblast growth factor 21 gene is an underlying cause of acinar cell injury in mice lacking MIST1

“…Studies to date have focused on the direct transcriptional targets of MIST1 and have identified several genes involved in acinar cell biology, including Gjb1 (encodes Cx32), Atp2c2 (encodes SPCA2), Rab3d, and Rab26 (16,21,43,48). The fact that all of these genes can be linked to acinar cell exocytosis has led to a model in which MIST1 acts as a scaling factor, a type of transcription factor that enhances rather than initiates gene expression of a number of genes associated with a particular cell function (36).…”

A single transcription factor is sufficient to induce and maintain secretory cell architecture

“…We and others have shown that both MIST1 and its Drosophila ortholog, DIMMED, prefer binding to palindromic CATATG or CAGCTG E boxes, usually located within the first kilobase of the first intron of target genes (Park et al 2008;Garside et al 2010;Tian et al 2010;Direnzo et al 2012;Hadzic et al 2015). Using the ChIP-seq analysis of MIST1 binding to acinar cell genomic DNA, we analyzed the location of the significant peaks in our list of putative target genes.…”

RAB26 coordinates lysosome traffic and mitochondrial localization

“…MIST1 expression is a feature of all serous exocrine cells (Lemercier et al, 1997;Pin et al, 2000). Recent work has begun to identify the molecular targets that it scales up to establish a high-capacity polarized secretory apparatus (Capoccia et al, 2013;Direnzo et al, 2012;Garside et al, 2010;Jia et al, 2008;Johnson et al, 2004;Pin et al, 2001;Rukstalis et al, 2003;Tian et al, 2010). For example, RAB3D has been identified as a target in both pancreatic and gastric exocrine cells (Johnson et al, 2004;Tian et al, 2010).…”