Leukemia inhibitory factor induces DNA synthesis in Swiss mouse 3T3 cells independently of cyclin D1 expression through a mechanism involving MEK/ERK1/2 activation.
Leukemia inhibitory factor (LIF) and oncostatin M (OSM) induce DNA synthesis in Swiss 3T3 cells through common signaling mechanism(s), whereas other related cytokines such as interleukin-6 and ciliary neurotrophic factor do not cause this response. Induction of DNA replication by LIF or prostaglandin F2alpha (PGF2alpha) occurs, in part, through different signaling events. LIF and OSM specifically trigger STAT1 cytoplasmic to nuclear translocation, whereas PGF2alpha fails to do so. However, LIF and PGF2alpha can trigger increases in ERK1/2 activity, which are required for their mitogenic responses because U0126, a MEK1/2 inhibitor, prevents both ERK1/2 activation and induction of DNA synthesis by LIF or PGF2alpha treatment. PGF2alpha induces cyclin D expression 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 full phosphorylation of retinoblastoma protein (Rb). However, both LIF and PGF2alpha increase cyclin E expression. Furthermore, LIF mitogenic action does not involve protein kinase C (PKC) activation, because a PKC inhibitor does not block this effect. In contrast, PKC activity is required for PGF2alpha mitogenic action. More importantly, the synergistic effect between LIF and PGF2alpha to promote S phase entry is independent of PKC activation. These results show fundamental differences between LIF- and PGF2alpha-dependent mechanism(s) that induce cellular entry into S phase. These findings are critical in understanding how LIF and other related cytokine-regulated events participate in normal cell cycle control and may also provide clues to unravel crucial processes underlying cancerous cell division.
Dekanty
Andres
A
Fundación Instituto Leloir, Av. Patricias Argentinas 435, 1405 Buenos Aires, Argentina.
Sauane
Moira
M
Cadenas
Belen
B
Coluccio
Federico
F
Barrio
Marcela
M
Casala
Jorgelina
J
Paciencia
Mercedes
M
Rogers
Florencia
F
Coso
Omar A
OA
Piwien-Pilipuk
Graciela
G
Rudland
Philip S
PS
de Asúa
Luis Jiménez
LJ
D000818:Animals; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000502:physiology; D004261:DNA Replication / Q000502:physiology*; D015237:Dinoprost / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology*; D007700:Kinetics; D053605:Leukemia Inhibitory Factor; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism* / Q000502:physiology; D053683:Oncostatin M; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D041701:Swiss 3T3 Cells
C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D016207:Cytokines; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C508352:Osm protein, mouse; D016160:Retinoblastoma Protein; D050791:STAT Transcription Factors; D053683:Oncostatin M; D019938:Cyclin D1; D015237:Dinoprost; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases