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J. Biol. Chem., Vol. 281, Issue 10, 6136-6143, March 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/10/6136    most recent M505839200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dekanty, A. Articles by de Asúa, L. J. Search for Related Content PubMed PubMed Citation Articles by Dekanty, A. Articles by de Asúa, L. J. Social Bookmarking                      What's this?

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

Andres Dekanty, Moira Sauane, Belen Cadenas, Federico Coluccio, Marcela Barrio, Jorgelina Casala, Mercedes Paciencia, Florencia Rogers¹, Omar A. Coso², Graciela Piwien-Pilipuk², Philip S. Rudland^¶, and Luis Jiménez de Asúa²³⁴

From the Fundación Instituto Leloir, Av. Patricias Argentinas 435, 1405 Buenos Aires, Argentina, Laboratorio de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina, and ^¶Molecular Medicine Group, School of Biological Sciences, University of Liverpool, Liverpool L69 3BX, United Kingdom

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 F₂ (PGF₂) occurs, in part, through different signaling events. LIF and OSM specifically trigger STAT1 cytoplasmic to nuclear translocation, whereas PGF₂ fails to do so. However, LIF and PGF₂ 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 PGF₂ treatment. PGF₂ 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 PGF₂ 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 PGF₂ mitogenic action. More importantly, the synergistic effect between LIF and PGF₂ to promote S phase entry is independent of PKC activation. These results show fundamental differences between LIF- and PGF₂-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.

Received for publication, May 27, 2005 , and in revised form, October 7, 2005.

^* This work was supported in part by the Association for International Cancer Research Grant 099-018 (Scotland, UK) and Cancer and Polio Research Fund (Liverpool, UK) (to L. J. A. and P. S. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a GlaxoSmithKline-Argentina fellowship.

² Investigator of the National Research Council (CONICET) of Argentina.

⁴ Visiting Professor from the Royal Society of London, School of Biological Sciences University of Liverpool, Liverpool, UK.

³ To whom correspondence should be addressed: Fundación Instituto Leloir, Av. Patricias Argentinas 435, C1405BWE Buenos Aires, Argentina. Tel.: 54-11-5238-7500; Fax: 54-11-5238-7501; E-mail: Ljimeneza{at}leloir.org.ar.

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