Growth hormone induces expression of c-jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c-fos oncogene expression.
Although the structure of several members of the GH receptor family has been defined, signal transduction following GH binding to its receptor has not been elucidated. Mouse osteoblasts were used to study the effect of GH on immediate early gene expression and, subsequently, the cellular signal(s) mediating this expression were analysed. GH rapidly and transiently induced the expression of c-jun and jun B in concert with the already reported expression of c-fos. The GH-induced expression of c-fos was completely blocked by the protein kinase inhibitors staurosporine and H7, indicating that the action of GH is mediated by one or several protein kinases. We next analysed the identity of the putative protein kinases in more detail by using a more specific protein kinase inhibitor, namely the ether-lipid 1-O-alkyl-2-O-methylglycerol, understood to be an inhibitor of protein kinase C (PKC). Data obtained from these studies revealed that GH-induced expression of c-fos is mediated by PKC. In addition, we observed a profound increase in formation of the PKC activator diacyglycerol upon addition of GH, a natural activator of PKC. In conclusion, upon binding of GH to mouse osteoblasts, the receptor-mediated cellular signal involves diacyglycerol formation and activation of PKC, leading to the induction of oncogene expression. Finally, the expression of c-fos, c-jun and jun B results in an increased binding of protein complexes to AP-1 binding sites.
Slootweg
M C
MC
Department of Internal Medicine, University Hospital, Utrecht, The Netherlands.
de Groot
R P
RP
Herrmann-Erlee
M P
MP
Koornneef
I
I
Kruijer
W
W
Kramer
Y M
YM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D013006:Growth Hormone / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D016759:Oncogene Protein p65(gag-jun); D009857:Oncogenes / Q000187:drug effects*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics*; D015398:Signal Transduction; D019311:Staurosporine; D014157:Transcription Factors / Q000235:genetics*
D000470:Alkaloids; D004268:DNA-Binding Proteins; D007546:Isoquinolines; D015345:Oligonucleotide Probes; D016759:Oncogene Protein p65(gag-jun); D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine