Colony-stimulating factor-1 receptor utilizes multiple signaling pathways to induce cyclin D2 expression

Colony-stimulating factor-1 (CSF-1) induces expression of immediate early g ene, such as c-myc and c-fos and delayed early genes such as D-type cyclins (D1 and D2), whose products play essential roles in the G1 to S phase tran sition of the cell cycle. Little is known, however, about the cytoplasmic s ignal transduction pathways that connect the surface CSF-1 receptor to thes e genes in the nucleus. We have investigated the signaling mechanism of CSF -1-induced D2 expression. Analyses of CSF-1 receptor autophosphorylation mu tants show that, although certain individual mutation has a partial inhibit ory effect, only multiple combined mutations completely block induction of D2 in response to CSF-1. We report that at least three parallel pathways, t he Src pathway, the MAPK/ERK kinase (MEK)/extracellular signal-regulated ki nase (ERK) pathway, and the c-myc pathway, are involved. Induction of D2 is partially inhibited in Src(-/-) bone marrow-derived macrophages and by Src inhibitor PP1 and is enhanced in v-Src-overexpressing cells. Activation of myc's transactivating activity selectively induces D2 but not D1. Blockade of c-myc expression partially blocks CSF-l-induced D2 expression. Complete inhibition of the MEK/ERK pathway causes 50%: decrease of D2 expression. F inally, simultaneous inhibition of Src, MEK activation, and c-myc expressio n additively blocks CSF-l-induced D2 expression. This study indicates that multiple signaling pathways are involved in full induction of a single gene , and this finding may also apply broadly to other growth factor-inducible genes.