The cellular protooncogenes c-fos and egr-1 are regulated by prostacyclin in rodent osteoblasts and fibroblasts.
PGs are local regulators of various cellular functions. They exert their effects via specific PG receptor subtypes. Induction of c-fos gene expression has been described for arachidonic acid and its metabolite PGE2. We demonstrate that another very short half-lifed prostanoid metabolite, namely prostacyclin (PGI2), is a regulator of immediate-early genes. PGI2 transiently induced the growth-associated immediate-early genes c-fos and egr-1 in osteoblastic as well as fibroblastic cell lines. Furthermore, we showed that PGI2 dose dependently stimulated new DNA synthesis in the osteoblastic cell line MC3T3-E1. Although PGI2 is known to be a potent inducer of cyclooxygenases, we showed that this pathway is not necessary for protooncogene induction by PGI2. Our data indicate a direct effect of PGI2 on immediate-early gene expression, which does not depend on the synthesis of other prostanoids. Intracellular signal transduction mechanisms were studied with the protein kinase inhibitor H-7, a potent inhibitor of PGI2-induced c-fos expression. Experiments with phorbol esters revealed that protein kinase C activity is not obligatory for the effect of PGI2 on c-fos expression. We conclude from these results that PGI2, a rapidly inactivated prostanoid, has a major impact on cellular oncogene expression and growth in mesenchymally derived cells.
Glantschnig
H
H
Ludwig Boltzmann Institute of Osteology, Fourth Medical Department, Hanusch Hospital, Vienna, Austria.
Varga
F
F
Klaushofer
K
K
D016475:3T3 Cells; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1; D011464:Epoprostenol / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016762:Genes, fos / Q000187:drug effects; D017874:Immediate-Early Proteins; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D012516:Osteosarcoma; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011519:Proto-Oncogenes / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D016718:Arachidonic Acid; D011464:Epoprostenol; D013936:Thymidine