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 gene, 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 transition of the cell cycle. Little is known, however, about the cytoplasmic signal transduction pathways that connect the surface CSF-1 receptor to these genes in the nucleus. We have investigated the signaling mechanism of CSF-1-induced D2 expression. Analyses of CSF-1 receptor autophosphorylation mutants show that, although certain individual mutation has a partial inhibitory effect, only multiple combined mutations completely block induction of D2 in response to CSF-1. We report that at least three parallel pathways, the Src pathway, the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (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-1-induced D2 expression. Complete inhibition of the MEK/ERK pathway causes 50% decrease of D2 expression. Finally, simultaneous inhibition of Src, MEK activation, and c-myc expression additively blocks CSF-1-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.

Dey A ，She H ，Kim L ，Boruch A ，Guris DL ，Carlberg K ，Sebti SM ，Woodley DT ，Imamoto A ，Li W ... -  《MOLECULAR BIOLOGY OF THE CELL》

Complementation of defective colony-stimulating factor 1 receptor signaling and mitogenesis by Raf and v-Src.

Aziz N ，Cherwinski H ，McMahon M 《-》

CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells.

Lee AW ，Nambirajan S ，Moffat JG 《ONCOGENE》

Regulation of cell cycle entry and G1 progression by CSF-1.

Roussel MF 《MOLECULAR REPRODUCTION AND DEVELOPMENT》

Cell cycle-independent induction of D1 and D2 cyclin expression, but not cyclin-Cdk complex formation or Rb phosphorylation, by IFNgamma in macrophages.

Dey A ，Li W 《-》