Activation of mouse osteoblast growth hormone receptor: c-fos oncogene expression independent of phosphoinositide breakdown and cyclic AMP.
Addition of human GH (hGH) to primary mouse osteoblasts resulted in rapid and transient induction of the c-fos and c-myc proto-oncogenes and preceded hGH-induced mitogenesis. Human GH-induced c-fos expression was maximal after 30 min, resulting in a 10- to 15-fold increase over unstimulated cells, and returned to prestimulation levels within 60 min of the addition of hGH. Induction of the c-fos gene by hGH was dose dependent and also occurred in the absence of protein synthesis, resulting in superinduction of the c-fos gene. The induction of the c-fos gene by hGH was mediated by a somatotrophic (GH) rather than a lactogenic (prolactin) receptor on primary mouse osteoblasts, as indicated by a 10- to 100-fold greater potency of hGH compared with ovine prolactin in stimulating the expression of the c-fos gene. Primary mouse osteoblasts also induced the c-fos gene in response to epidermal growth factor, insulin-like growth factor-I and several agents, including phorbol 12-myristate 13-acetate (TPA), forskolin and A23187, that are known to activate signal transduction pathways involved in the action of growth factors. Addition of hGH to primary mouse osteoblasts did not result in increased phosphoinositide breakdown, while selective deactivation of the diacylglycerol-protein kinase C and inositol 1,4,5-trisphosphate-Ca2+ pathways by long-term TPA pretreatment or depleting intracellular Ca2+ stores had no effect on hGH-induced c-fos expression. Human GH did not alter basal cyclic AMP levels in mouse osteoblasts. The immediate consequences of GH-receptor interaction as well as the mechanism of signal transduction leading to induction of the c-fos gene remain, therefore, unresolved.
Slootweg
M C
MC
University Hospital, Department of Internal Medicine, Utrecht, The Netherlands.
van Genesen
S T
ST
Otte
A P
AP
Duursma
S A
SA
Kruijer
W
W
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D011519:Proto-Oncogenes; D011981:Receptors, Prolactin / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D010716:Phosphatidylinositols; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011981:Receptors, Prolactin; D011986:Receptors, Somatotropin; D013006:Growth Hormone; D000242:Cyclic AMP