title: Ras- and Raf-mediated regulation of transforming growth factor beta 1 gene expression by ligands of tyrosine kinase receptors in PC12 cells.
abstract: Different ligands of tyrosine kinase receptors have neurotrophic or mitogenic effects in PC12 cells. NFG and FGF, which cause morphological differentiation, as well as EGF, that induces cell growth, produce a significant increase of TGF-beta1 transcripts in PC12 cells. Sequences responsible for the transcriptional effects of the growth factors are located in the 5'-flanking region of the TGF-beta1 gene. The TGF-beta1 gene has two promoters and the growth factors significantly enhance the activity of constructs containing either the first or the second promoter. A functional p21ras is required for the regulation of TGF-beta1 by ligands of tyrosine kinase receptors since expression of oncogenic ras in PC12 cells also increases TGF-beta1 transcripts, and a dominant inhibitory ras mutant blocks activation of TGF-beta1 gene expression by NGF. Oncogenic raf stimulates the activity of both promoters and a dominant negative raf also significantly inhibits growth factor activation. As determined by Mv1Lu cell proliferation inhibition assay, PC12 cells release a significant amount of TGF-beta1 in a latent form and incubation with growth factors or expression of oncogenic ras further increase TCF-beta1 production. These results suggest that during proliferation or growth factor-induced differentiation of sympathetic neurons there is an increase in TGF-beta1 that could be an important mediator of neural cells function.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Cosgaya
authors.forename: A
authors.initials: A
authors.lastname: Aranda
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D003470:Culture Media / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics; D051766:Early Growth Response Protein 1; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D017874:Immediate-Early Proteins; D009154:Mutation; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology; D027384:Oncogene Proteins v-raf; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D003470:Culture Media; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf