GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR ABROGATES TRANSFORMING GROWTH FACTOR-BETA-1-MEDIATED CELL-CYCLE ARREST BY UP-REGULATING CYCLIN D2 CDK6

The role of positive and negative cytokine interactions in G1 cell cyc le regulation of haemopoietic cells was analysed by determination of t he expression patterns of D-type cyclins and cyclin-dependent kinases (cdks) in SKM-1 myelodysplastic syndrome (MDS) cells incubated with gr anulocyte-macrophage colony-stimulating factor (GM-CSF) and/or transfo rming growth factor-beta 1 (TGF-beta 1). TGF-beta 1 inhibited SKM-1 ce ll proliferation due to the cell cycle arrest in G1 phase. GM-CSF abro gated the TGF-beta 1-mediated G1 arrest in these cells. Reverse transc ription-polymerase chain reaction (RT-PCR) analysis indicated that TGF -beta 1-mediated G1 arrest correlated with the down-regulation of cdk4 , cdk6 and cyclin D2, and that abrogation of TGF-beta 1-mediated G1 ar rest by GM-CSF correlated with the constitutive over-expression of cyc lin D2 and cdk6 but not cdk4. These results suggest the importance of cyclin D2/cdk6 levels in abrogating G1 arrest in cells exposed to TGP- beta 1, and raise the possibility that the GM-CSF-mediated up-regulato ry pathway of signal transduction through cyclin D2/cdk6 differs from the TGF-beta 1-cdk4-mediated pathway in SKM-1 cells. This signal trans duction pathway through cyclin D2/cdk6 might play an important role in haemopoietic regulation by the cytokine network.