Leukaemia inhibitory factor (LIF) and Oncostatin M (OSM) induce DNA synthesis in Swiss 3T3 cells through common signaling mechanism(s), whilst other related cytokines such as Interleukin-6 (IL-6) and Cilliary Neutrophic Factor (CNTF) do not cause this response. Induction of DNA replication by LIF or Prostaglandin F2a(PGF2a) occurs, in part, through different signaling events. LIF and OSM specifically trigger STAT1 cytoplasmic to nuclear translocation, whereas PGF2a fails to do so. However LIF and PGF2a can trigger increases in ERK1/2 activity, which are required for their mitogenic responses since U0126, a MEK1/2 inhibitor, prevents both ERK1/2 activation and induction of DNA synthesis by LIF or PGF2a treatment. PGF2a induces cyclins D expression and full phosphorylation of Rb. In contrast, LIF fails to promote increases in cyclins D mRNA/protein levels and, consequently, LIF induces DNA synthesis without promoting full phosphorylation of Rb. However, both LIF and PGF2a increase cyclin E expression. Further, LIF mitogenic action does not involve protein kinase C (PKC) activation, since a PKC inhibitor does not block this effect. In contrast, PKC activity is required for PGF2a mitogenic action. Importantly, the sinergistic effect between LIF and PGF2a to promote S-phase entry is independent of PKC activation. These results show fundamental differences between LIF- and PGF2a- dependent mechanism(s) that induces cellular entry into S-phase. These findings are critical in understanding how LIF and other related cytokines regulated events participate in normal cell cycle control, and may also provide clues to unravel crucial processes underlying cancerous cell division.