STRUCTURE AND REGULATION OF THE MOUSE GRP78 (BIP) PROMOTER BY GLUCOSEAND CALCIUM IONOPHORE

Dietary calorie restriction, also termed energy restriction, increases mean and maximum life span, reduces the incidence of tumors and incre ases the mean age of onset of diseases and tumors in every animal test ed. Because life-span is genetically determined, we are studying the m echanisms by which energy restriction regulates the expression of gene s. We found that energy restriction reduces hepatic glucose-regulated protein-78 (GRP78) and protein-94 mRNA levels by 2-3-fold in mice [Spi ndler et al., J. Nutr. 20 (1990) 1412-1417]. To investigate this down- regulation, we have cloned the mouse GRP78 promoter (pGRP78) and studi ed its regulation by glucose. The mouse pGRP78 and the previously clon ed rat promoter mediate responsiveness to glucose deprivation, as well as to the calcium ionophore A23187. These studies are the first demon stration that cis-elements in the pGRP78 mediate responsiveness to glu cose deprivation.