Stimulation of GRP78 gene transcription by phorbol ester and cAMP in GH sub(3) pituitary cells: The accommodation of protein synthesis to chronic deprivation of intracellular sequestered calcium

GRP78/BiP resides in the lumen of the endoplasmic reticulum (ER), a major site of Ca super(2+) sequestration and early protein processing. Agents, such as ionophore A23187, that mobilize sequestered ER Ca super(2+) suppress translational initiation within minutes and induce GRP78 within 1-3 h accompanied by development of translational tolerance to the inhibitor. Accommodation is prevented by actinomycin D and reduced by antisense oligonucleotides directed against GRP78 mRNA. In GH sub(3) cells, optimal induction of GRP78 and translational accommodation depended on cAMP elevation and phorbol ester. GRP78 mRNA was induced 3 - 6-fold with A23187 alone as compared with 12 - 20-fold with ionophore plus cAMP-elevating agent and phorbol ester, but was not markedly induced without A23187. GRP78 gene transcription in nuclei isolated from A23187-treated cells was increased 2 - 4-fold by cAMP and phorbol ester.