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Molecular and Cellular Biology, January 2003, p. 543-554, Vol. 23, No. 2
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.2.543-554.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Ras/Raf/MEK/Extracellular Signal-Regulated Kinase Pathway Induces Autocrine-Paracrine Growth Inhibition via the Leukemia Inhibitory Factor/JAK/STAT Pathway

Jong-In Park,1 Christopher J. Strock,1 Douglas W. Ball,1,2 and Barry D. Nelkin1*

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,1 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 212312

Received 9 July 2002/ Returned for modification 18 September 2002/ Accepted 22 October 2002

Sustained activation of the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway can lead to cell cycle arrest in many cell types. We have found, with human medullary thyroid cancer (MTC) cells, that activated Ras or c-Raf-1 can induce growth arrest by producing and secreting an autocrine-paracrine factor. This protein was purified from cell culture medium conditioned by Raf-activated MTC cells and was identified by mass spectrometry as leukemia inhibitory factor (LIF). LIF expression upon Raf activation and subsequent activation of JAK-STAT3 was also observed in small cell lung carcinoma cells, suggesting that this autocrine-paracrine signaling may be a common response to Ras/Raf activation. LIF was sufficient to induce growth arrest and differentiation of MTC cells. This effect was mediated through the gp130/JAK/STAT3 pathway, since anti-gp130 blocking antibody or dominant-negative STAT3 blocked the effects of LIF. Thus, LIF expression provides a novel mechanism allowing Ras/Raf signaling to activate the JAK-STAT3 pathway. In addition to this cell-extrinsic growth inhibitory pathway, we find that the Ras/Raf/MEK/ERK pathway induces an intracellular growth inhibitory signal, independent of the LIF/JAK/STAT3 pathway. Therefore, activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest and differentiation via at least two different signaling pathways. This use of multiple pathways may be important for "fail-safe" induction and maintenance of cell cycle arrest.

* Corresponding author. Mailing address: Rm. 552, 1650 Orleans St., Baltimore, MD 21231. Phone: (410) 955-8506. Fax: (410) 614-9884. E-mail: bnelkin{at}jhmi.edu.

Molecular and Cellular Biology, January 2003, p. 543-554, Vol. 23, No. 2
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.2.543-554.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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