Mechanism of differential inhibition of factor-dependent cell proliferation by transforming growth factor-beta 1: selective uncoupling of FMS from MYC.
Transforming growth factor-beta 1 (TGF-beta 1) selectively modulates hematopoietic cell proliferation. The proliferation of FDC-P1 clone MAC-11, a factor-dependent murine myeloid progenitor cell line, was inhibited differentially by TGF-beta 1: strongly in macrophage colony-stimulating factor (M-CSF), mildly in interleukin-3, and not at all in granulocyte-macrophage-CSF (GM-CSF). Flow cytometry and Western blots showed an unexpected increase in expression of FMS, the receptor for M-CSF, in response to TGF-beta 1. Metabolic labeling with 35S-methionine showed that synthesis of FMS protein accelerated in response to TGF-beta 1, whereas its degradation was unaffected. Northern analyses showed a rapid increase in c-fms RNA after the addition of TGF-beta 1. TGF-beta 1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS. However, TGF-beta 1 inhibited the induction by M-CSF of c-myc RNA analyzed on Northern blots and protein detected by radioimmuno-precipitation. TGF-beta 1 did not affect induction of c-myc expression by GM-CSF or induction of c-fos or c-jun by M-CSF. Therefore, FMS and the GM-CSF receptor induce c-myc via signal transduction pathways that differ in that only the former is inhibited by TGF-beta 1. This inhibition may account for the selective growth regulation by TGF-beta 1.
Chen
A R
AR
Department of Cell Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
Rohrschneider
L R
LR
D000199:Actins / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000032:analysis / Q000378:metabolism; D016236:Genes, fms / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D000199:Actins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D011505:Protein-Tyrosine Kinases