Leukemia Inhibitory Factor Induces DNA Synthesis in Swiss Mouse 3T3 Cells Independently of Cyclin D1 Expression through a Mechanism Involving MEK/ERK1/2 Activation

DEKANTY, A.; SAUANE, M.; CADENAS, B.; COLUCCIO, F.; BARRIO, M.; CASALA, J.; PACIENCIA, M.; ROGERS, F.; COSO, O. A.; PIWIEN-PILIPUK, G..; RUDLAND, P. S.; DE ASUA, L. J.

JOURNAL OF BIOLOGICAL CHEMISTRY

Año: 2006 p. 6135 - 6143

0021-9258

AbstractLeukemia inhibitory factor (LIF) and oncostatin M (OSM) induceDNA synthesis in Swiss 3T3 cells through common signaling mechanism(s), whereas other related cytokines such as interleukin-6 and ciliaryneurotrophic factor do not cause this response. Induction ofDNAreplication by LIF or prostaglandin F2 (PGF2) occurs, in part,through different signaling events. LIF and OSM specifically triggerSTAT1cytoplasmictonucleartranslocation,whereasPGF2failstodoso. However, LIF and PGF2 can trigger increases in ERK1/2 activity,which are required for their mitogenic responses because U0126, aMEK1/2 inhibitor, prevents both ERK1/2 activation and induction ofDNA synthesis by LIF or PGF2 treatment. PGF2 induces cyclin Dexpression and full phosphorylation of retinoblastoma protein. In contrast,LIF fails to promote increases in cyclin D mRNA/protein levels;consequently, LIF induces DNA synthesis without promoting fullphosphorylation of retinoblastoma protein (Rb). However, both LIFand PGF2 increase cyclin E expression. Furthermore, LIF mitogenicaction does not involve protein kinase C (PKC) activation, because aPKC inhibitor does not block this effect. In contrast, PKC activity isrequired for PGF2mitogenic action. More importantly, the synergisticeffectbetweenLIFandPGF2topromoteSphaseentryisindependentof PKC activation. These results show fundamental differencesbetweenLIF-andPGF2-dependentmechanism(s)thatinducecellularentryintoSphase.ThesefindingsarecriticalinunderstandinghowLIFand other related cytokine-regulated events participate in normal cellcycle control and may also provide clues to unravel crucial processesunderlying cancerous cell division.