Regulation of CYL/cyclin D genes by colony-stimulating factor 1

The proliferative effects of colony-stimulating factor 1 (CSF-1) on macrophages are exerted only throughout the G1 phase of the cell cycle. Genetic targets of the delayed early response to CSF-1 include novel G1 cyclin (CYL or cyclin D) genes. In macrophages, cyclin D1 is induced early in G1 and is expressed throughout the cell cycle as long as CSF-1 is present. The cyclin D1 protein turns over rapidly in CSF-1-stimulated cells and its level declines precipitously upon CSF-1 withdrawal. Cyclin D2 is induced later in G1 and its expression is periodic, whereas cyclin D3 is not expressed in macrophages but is regulated by growth factors in other cell types. The cyclin D1 protein associates during G1 with a polypeptide antigenically related to p34cdc2 and binds in vitro to a histone H1 kinase present in lysates of CSF-1-starved macrophages. The instability of the cyclin D1 protein and its ability to rescue a cyclin-dependent kinase activity from growth factor-deprived macrophages together suggest that the cyclin D protein is the dynamic partner in the complex. The timing of expression of cyclin D genes suggests that they act to link growth factor signals with cell cycle transitions during G1.