RAPID COMMUNICATION Involvement of p2lCip-' and p27kip-1 in the Molecular Mechanisms of Steel Factor-Induced Proliferative Synergy In Vitro and of p2lCip" in the Maintenance of Stem/Progenitor Cells In Vivo

Steel factor ELF) is a hematopoietic cytokine that synergizes with other growth factors to induce a greatly enhanced proliferative state of hematopoietic progenitor cells and factor-dependent cell lines. Even though the in vivo importance of SLF in the maintenance and responsiveness of stem and progenitor cells is well documented, the molecular mechanisms involved in its synergistic effects are mainly unknown. Some factor-dependent myeloid cell lines respond to the synergistic proliferative effects of SLF plus other cytokines in a manner similar to that of normal myeloid progenitor cells from bone marrow and cord blood. We show here that SLF can synergize with granulocyte-macrophage colonystimulating factor (GM-CSF) t o induce an enhanced phosphorylation of the retinoblastoma gene product and a synergistic increase in the total intracellular protein level of the cyclin-dependent kinase inhibitor, p21"'P'. which is correlated with a simultaneous decrease in p27"P' in the human factor-dependent myeloid cell line, M07e. Moreover, these cytokines synergize t o increase p2lCip-' binding and decrease ~ 2 7 " ~ ' binding to cyclin-dependent kinase-2 (cdk2), an enzyme required for normal cell cycle progression; these in-