Evidence that ras and myc mediate the synergy between SCF or M-CSF and other haemopoietic growth factors.
We previously reported that M-CSF could mimic the synergistic effect of SCF upon myeloid FDC-P1 cells that were first infected with a c-fms retrovirus, which encodes the human M-CSFr. We now report that an M-CSFr with a mutation of its autophosphorylation site at position 809 was, in response to M-CSF, unable both to synergize with IL-3 or GM-CSF and to induce c-myc; whereas a mutant receptor with a deletion of its kinase insert was unaffected for these processes. The expression of an exogenous c-myc proto-oncogene or a 12H-ras oncogene lowered the requirement of FDC-P1 cells for IL-3 or GM-CSF, in a similar manner to M-CSF or SCF addition. Furthermore, the expression of either of these genes complemented the defective M-CSFr F809. These results strongly support a role for ras and myc in the synergistic action of M-CSF and, by implication, of SCF, which implies that these signalling intermediates are rate-limiting for the action of IL-3 and GM-CSF and possibly other haemopoietic growth factors.
Baker
D A
DA
Department of Haematology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Maher
J
J
Roberts
I A
IA
Dibb
N J
NJ
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression; D016259:Genes, myc; D011905:Genes, ras; D006133:Growth Substances / Q000494:pharmacology*; D016298:Hematopoietic Cell Growth Factors / Q000008:administration & dosage*; D016173:Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D019000:Phosphotyrosine; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D006133:Growth Substances; D016298:Hematopoietic Cell Growth Factors; C000715470:MAS1 protein, human; D009838:Oligodeoxyribonucleotides; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D019089:Stem Cell Factor; D019000:Phosphotyrosine; D014443:Tyrosine; D016173:Macrophage Colony-Stimulating Factor; D020794:Receptor Protein-Tyrosine Kinases