Mechanism of differential inhibition of factor-dependent cell proliferation by transforming growth factor-β1: Selective uncoupling of FMS from MYC

Transforming growth factor-β1 (TGF-β1) 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-β1: 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-β1. Metabolic labeling with ³⁵S-methionine showed that synthesis of FMS protein accelerated in response to TGF-β1, whereas its degradation was unaffected. Northern analyses showed a rapid increase in c-fms RNA after the addition of TGF-β1. TGF-β1 did not affect kinase activity, cellular phosphotyrosine response, or internalization of FMS. However, TGF-β1 inhibited the induction of M-CSF of c-myc RNA analyzed on Northern blots and protein detected by radioimmunoprecipitation. TGF-β1 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-β1. This inhibition may account for the selective growth regulation by TGF-β1.