MIST1 regulates the pancreatic acinar cell expression of Atp2c2, the gene encoding secretory pathway calcium ATPase 2.
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 Ca(2+) signaling that are normally controlled by acinar cell Ca(2+)-ATPases. Previous studies indicated that total sarcoendoplasmic reticulum Ca(2+)-ATPases (SERCA) and plasma membrane Ca(2+)-ATPases (PMCA) remained unaffected in Mist1(-/-) acinar cultures. Therefore, we have assessed the expression of Atp2c2, the gene that encodes the secretory pathway Ca(2+)-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.
Garside
Victoria C
VC
Children's Health Research Institute, London, Ontario, Canada.
Kowalik
Agnes S
AS
Johnson
Charis L
CL
DiRenzo
Daniel
D
Konieczny
Stephen F
SF
Pin
Christopher L
CL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D012469:Salivary Glands / Q000737:chemistry; D012669:Seminal Vesicles / Q000737:chemistry
D051792:Basic Helix-Loop-Helix Proteins; D000252:Calcium-Transporting ATPases; D012333:RNA, Messenger; C491312:Bhlha15 protein, mouse; C528285:SPCA2 protein, mouse