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

Abstract

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 autocrineparacrine 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.

Alterations in alveolar epithelium differentiation and vasculogenesis in lungs of LIF/IGF‐I double deficient embryos

“…Conversely, LIF induces phosphorylation of insulin receptor substrates, and activation of both MAPK and PI3K/Akt pathways (Argetsinger et al, 1995;Oh et al, 1998;Turnley and Bartlett, 2000). Activation of the Ras/MAPK pathway induces LIF synthesis and activation of JAK/STAT3 in lung carcinoma cells (Park et al, 2003). The other way around, activation of STATs regulates SP-B in the lung and IGF-I in fibroblasts and myoblasts (Frost et al, 2002;Hwa et al, 2004;Yang et al, 2004).…”

A Key Role for Leukemia Inhibitory Factor in C26 Cancer Cachexia

“…ERK Signaling in C26 CM-The ERK pathway has also been implicated in C26 cachexia and is a known signaling arm of LIF (28). Although no reporter system for activated transcription factors in this pathway was available, we tested U0126, a known inhibitor of ERK activation by MEK (28).…”

“…Although no reporter system for activated transcription factors in this pathway was available, we tested U0126, a known inhibitor of ERK activation by MEK (28). U0126 at 3 M was able to inhibit myotube atrophy because of C26 CM (Fig.…”

Small proline-rich proteins 2 are noncoordinately upregulated by IL-6/STAT3 signaling after bile duct ligation

“…An adenoviral vector coding for a dominant negative form of STAT3 (AdSTAT3-DN) and a control viral vector (AdGFP) (gifts from Dr J Park) were used to transiently transfect mouse BEC at a dose of 25 MOI. 30 The AdSTAT3-DN and the AdGFP express green fluorescent protein (GFP) used to measure viral titers and transfection efficiency.…”