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Mol Reprod Dev. 1997 Jan;46(1):11-8.

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

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Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.


Proliferation, differentiation, and survival of monocytes, macrophages, and their immediate progenitors is regulated by the macrophage colony-stimulating factor (CSF-1). CSF-1 initiates a mitogenic response by binding to its receptor (CSF-1R), thereby activating the receptor's intrinsic tyrosine kinase activity and initiating signaling via multiple effector-mediated pathways. CSF-1 is required throughout G1 to ensure entry of bone marrow-derived macrophages into S phase, and persistent CSF-1R kinase activity is necessary to the expression of both immediate early (e.g., c-fos, c-jun, and c-myc) and delayed early (e.g., D-type cyclins) response genes. Ectopic expression of human CSF-1R in different mouse cell lines, including fibroblasts, IL-3-dependent myeloid cells, and early pre-B cells, confers CSF-1 responsiveness by replacing the cells' requirements for other mitogenic growth factors. NIH-3T3 fibroblasts engineered to express a human CSF-1 receptor point mutant (CSF-1R [Y809F]) fail to proliferate in response to CSF-1 and remain arrested in the early G1 phase of the cell cycle. Despite CSF-1-dependent transcription of fos and jun family members, c-myc, D-type, and E-type G1 cyclin mRNAs are not expressed in the latter cells in response to growth factor stimulation. However, enforced expression of c-myc or D-type cyclins, but not cyclin E, resensitizes cells bearing CSF-1R (Y809F) to the mitogenic effects of CSF-1, enabling them to proliferate continuously in liquid culture and to form colonies in agar in response to the growth factor. D-type cyclin mutants defective in binding to the retinoblastoma protein (pRB) were unable to rescue mutant receptor signaling, suggesting that the ability of D-type cyclin-dependent kinases to cancel pRB's growth-suppressive function is necessary for CSF-1-induced G1 exit. By contrast, cyclin E must function in a different pathway. Cells rescued by c-myc were prevented from entering S phase by microinjection of antibodies to cyclin D1. Conversely, cyclin D1-rescued cells were inhibited from forming CSF-1-dependent colonies in agar when challenged with either a dominant-negative c-myc mutant or mad, a transcription factor which competes with myc for max, its requisite heterodimeric partner. Thus, although the expression of c-myc and D-type cyclins is rate limiting for G1 phase progression, their functions are interdependent, with both activities being required for mitogenicity.

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