Requirement for MAP Kinase (ERK2) Activity in Interferon α- and Interferon β-Stimulated Gene Expression Through STAT Proteins

David, Michael; Petricoin, Emanuel; Benjamin, Christopher D.; Pine, Richard; Weber, Michael J.; Larner, Andrew C.

doi:10.1126/science.7569900

Cited by 539 publications

(373 citation statements)

References 12 publications

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“…To this regard, type I IFNs have been shown to stimulate Raf and ERK activation in a Jak-dependent, but Ras-independent manner (Stancato et al, 1997;Sakatsume al, 1998). The cross-talk between the Jak/STAT and MEK/ERK pathway is further demonstrated by observation that stimulation with IFN-β can result in activation of ERK and its direct association with STAT1, as revealed by co-immunoprecipitation studies (David et al, 1995). In other reports IFN-α has been shown to directly activate MEK/ERK (Arora et al, 1999;Lund et al, 1999) and phosphatidylinositol 3-kinase (PI-3K) (Uddin et al, 1997).…”

Section: Discussionmentioning

confidence: 94%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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Summary Interferon (IFN)-α affects the growth, differentiation and function of various cell types by transducing regulatory signals through the Janus tyrosine kinase/signal transducers of activation and transcription (Jak/STAT) pathway. The signalling pathways employing the mitogenactivated ERK-activating kinase (MEK) and the extracellular-regulated kinase (ERK) are critical in growth factors signalling. Engagement of the receptors, and subsequent stimulation of Ras and Raf, initiates a phosphorylative cascade leading to activation of several proteins among which MEK and ERK play a central role in routing signals critical in controlling cell development, activation and proliferation. We demonstrate here that 24-48 h following treatment of transformed T-and monocytoid cell lines with recombinant human IFN-α2b both the phosphorylation and activity of MEK1 and its substrates ERK1/2 were reduced. In contrast, the activities of the upstream molecules Ras and Raf-1 were not affected. No effect on MEK/ERK activity was observed upon short-term exposure (1-30 min) to IFN. The anti-proliferative effect of IFN-α was increased by the addition in the culture medium of a specific inhibitor of MEK, namely PD98059. In conclusion, our results indicate that IFN-α regulates the activity of the MEK/ERK pathway and consequently modulates cellular proliferation through a Ras/Raf-independent mechanism. Targeting the MEK/ERK pathway may strengthen the IFN-mediated anti-cancer effect.

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Section: Discussionmentioning

confidence: 94%

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

2000

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“…These data suggest that coordinated activation of distinct signaling pathways are required for the regulation of Bcl-x gene expression in response to cytokines. Cross-talk between the JAK/STAT and the Ras/MAP kinase pathways has been described, and MAP kinase has been shown to regulate the transcriptional activity of STAT3 and STAT5A by serine phosphorylation David et al, 1995;Pircher et al, 1997). The role of the MAP kinase on the serine phosphorylation of STAT5 in Ba/F3 cells after IL-3 stimulation remains to be elucidated however.…”

Section: Discussionmentioning

confidence: 99%

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

et al. 1999

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“…This could result in the serine phosphorylation of STAT5, necessary for its activation. However, if MAP serine kinases are indeed involved in STAT activation is still a matter of debate (David et al, 1995;Beadling et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

et al. 1998

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Overexpression of the mutationally activated Xmrk receptor initiates the formation of hereditary malignant melanoma in the ®sh Xiphophorus. In addition to transcriptional overexpression a cell-type speci®c signal transduction is essential for Xmrk mediated tumor formation. To elucidate the consequence of Xmrk signalling and to identify target proteins that characterize the tumor phenotype, we analysed proteins that are strongly tyrosine phosphorylated in the ®sh melanoma cell line PSM. One of the most prominent phosphotyrosine proteins was found to be the signal transducer and activator of transcription STAT5. In a heterologous cell system (murine pro B-cells), activation of the Xmrk kinase in a chimeric receptor induced tyrosine phosphorylation, nuclear translocation and DNA binding of STAT5. Following receptor stimulation, expression of the STAT5 speci®c target genes cis, osm and pim-1 was induced. In Xiphophorus PSM cells STAT5 was found to be preferentially localized in the nucleus, but treatment with tyrphostin AG555, a speci®c Xmrk kinase-inhibitor, blocked nuclear localization. In these cells as well as in Xiphophorus melanoma expression of pim-1 and constitutive DNA-binding activity of STAT5 was detectable. This constitutive activity was higher in malignant than in benign melanomas, indicating that STAT5 activation is correlated with the malignancy of these tumors.

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Requirement for MAP Kinase (ERK2) Activity in Interferon α- and Interferon β-Stimulated Gene Expression Through STAT Proteins

Cited by 539 publications

References 12 publications

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line

Signalling by the oncogenic receptor tyrosine kinase Xmrk leads to activation of STAT5 in Xiphophorus melanoma

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