HORMONAL-REGULATION OF PROTEIN DISULFIDE-ISOMERASE AND CHAPERONE SYNTHESIS IN THE RAT EXOCRINE PANCREAS

Folding and assembly of polypeptides translocated into the rough endop lasmic reticulum (RER) is fascilitated by a set of resident proteins i n the lumen of the RER. We studied the regulation of synthesis of the RER luminal proteins immunglobulin heavy chain binding protein (BiP) a nd protein disulfide isomerase (PDI), and of the cytosolic stress 70 p rotein (hsc70) after hormonal stimulation of the pancreatic exocrine s ecretory pathway. Their rate of synthesis was assessed at both mRNA an d protein levels and under two experimental conditions that are associ ated with large increases in exocrine production. After in vivo stimul ation of the pancreas by either endogenous release of cholecystokinin (CCK) following proteinase inhibitor feeding (FOY-305) or by in vivo i nfusion of the pancreatic secretagogue cerulein, the relative rates of synthesis detected for BiP and PDI were enhanced 2.5 to 4-fold compar ed to control. Interestingly, the kinetics and the degree of hsc70 mRN A induction were almost identical to those of BiP and PDI, suggesting coordinated hormonal regulation of BiP, PDI as hormonal stimulation wa s even twice that following heat shock treatment. The mRNA levels of c alreticulin (CaBP3) increased up to 2.3-fold with a kinetic comparable to that of BiP, PDI and hsc 70, while CaBP1 and the RER membrane prot eins, ribophorin I and the signal recognition particle receptor did no t show any changes in their relative mRNA amounts after hormonal stimu lation. The increase in the rates of PDI and chaperone biosynthesis ex ceeds the associated increase in total protein biosynthesis. In vitro experiments, using transformed rat acinar cells (AR4-2J) in which panc reatic enzyme synthesis can be induced by glycocorticoid hormones, dem onstrated that induction of PDI and chaperone mRNA synthesis preceded extensive mRNA expression of secretory proteins.