Brefeldin A, thapsigargin, and AlF stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis
✍ Scribed by Brendan D. Price; Laura A. Mannheim-Rodman; Stuart K. Calderwood
- Book ID
- 102881411
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 888 KB
- Volume
- 152
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
The glucose regulated proteins (GRPs) are major structural components of the endoplasmic reticulum (ER) and are involved in the import, folding, and processing of ER proteins. Expression of the glucose regulated proteins (CRP78 and GRP94) is greatly increawd after cells are exposed to stress agents (including A23187 and tunicamycin) which inhibit ER function. Here, we demonstrate that three novel inhibitors of EK function, thapsigargin (which inhibits the ER Ca2 ' +-ATPase), brefeldin A (an inhibitor of vesicle transport between the ER and Colgi) and AI F, , (which inhibits trimeric G-proteins), can increase theexpression of both GKP78 and 94. The common characteristic shared by activators of GRP expression is that they disrupt some function of the ER. The increased levels of GRPs may be a rebponse to the accumulation of aberrant proteins in the ER or they may be increased in response to structuralifunctional damage to the ER. The increased accumulation of GRP78 m R N A after exposure of cells to either thapsigargin, breieldin A, AI F, , A231 87, or tunicamycin can be blocked by pre-incubation in cyclohexiniide. In contrast, accumulation of CKPs after exposure to hypoxia was independent of cycloheximide. In addition, the protein kinase inhibitor genistein blocked the thapsigargin induced accumulation of GRP78 m R N A , whereas the protein phosphatase inhibitor okadaic acid caused increased accumulation of GRP78 mRNA. The data indicates that there are at least 2 mechanisms for induced expression of GRPs, one of which involves a phosphorylation step and requires new protein synthesis (e.g., thapsigargin, A 2 3 1 87) and one which is independent of both these steps (hypoxia). Q 1992 WiIey-Liss, Inc.