Pertussis toxin provides evidence for two independent signalling pathways leading to the activation of the nerve growth factor gene
✍ Scribed by D. Wion; I. Neveu; F. Jehan; P. Brachet
- Publisher
- John Wiley and Sons
- Year
- 1992
- Tongue
- English
- Weight
- 666 KB
- Volume
- 31
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Abstract
Increased expression of the nerve growth factor (NGF) gene may be obtained by treating L929 fibroblasts with serum, phorbol 12‐myristate 13‐acetate (PMA), or 1,25‐dihydroxyvitamin D3 (1,25‐(OH)~2~ D~3~). The possible involvement of GTP‐binding proteins (G proteins) in these regulatory events was monitored by exposing the cells to pertussis toxin (PT), a compound known to inactivate several types of G proteins by ADP ribosylation. Measurements of the I pool of NGF mRNA by Northern blot analysis, and quantification of the factor secreted by the cells with a double‐site ELISA assay, indicate that pretreatment with PT decreases by about 60% the effect of serum on the levels of NGF transcript and secreted factor. This effect is accompanied by a corresponding decrease of the expression of c‐fos gene, which takes place soon after the addition of serum to the cells. In contrast, PT had no effect on the basal level of NGF mRNA found in cells maintained in serum‐free medium or in cells stimulated with PMA or 1,25‐(OH)~2~D~3~. These results indicate that some serum factor(s) acts via plasma membrane receptors able to interact with PT‐sensitive G proteins to modulate NGF gene expression. In contrast, 1,25‐(OH)2D3 appears to mediate its action through a different signalling pathway, which is likely to require its cytosolic receptor, and is independent of PT‐sensitive G protein and c‐fos induction. PMA is thought to directly activate enzymes of the protein kinase C family, and would therefore bypass the step involving activation of these enzymes by a G‐proteindependent pathway. These results suggest that a dys function in the G protein(s) and c‐fos pathway involved in the regulation of NGF gene could lead to neuropathological processes by altering the expression of the NGF gene. In addition, 1,25‐(OH)~2~ D~3~, in light of its ability to bypass these pathways, could be of potential interest in the treatment of neurodegenerative diseases.