Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6.

Abstract

NF-IL6, a member of the basic leucine zipper (bZIP) family transcription factors, is involved in expression of inducible genes involved in immune and inflammatory responses. We observed that coexpression of oncogenic p2l1 stimulated the transactivating activity of NF-IL6 and induced phosphorylation of Thr-235 located just N-terminal NF-IL6 was initially identified as a nuclear factor binding to the interleukin 1 (IL-1) responsive element in the IL-6 gene (1). The cloned NF-IL6 exhibits a homology with CCAAT/ enhancer binding protein (C/EBP), a member of the basic leucine zipper (bZIP) family of transcription factors (2). This protein has recently been reported by other groups under the names AGP/EBP, LAP, IL-6DBP, rNFIL-6, C/EBPP3, and CRP2 (3-8). NF-IL6 activates several acute-phase protein genes through the IL-6 responsive elements, implying that it is a nuclear target for IL-6 signal transduction (5, 9). NF-IL6 has also been shown to be responsible for regulation of the genes encoding albumin, c-fos, and several adipocytespecific proteins. Furthermore, NF-IL6 has been implicated in activation of various genes involved in inflammatory and immune responses, including the IL-8, granulocyte/colonystimulating factor, IL-1, and immunoglobulin genes (10). Thus, NF-IL6 has turned out to be a pleiotropic transactivator involved in signal transduction and cell differentiation.The signal transduction pathway mediated by growth factors and cytokines is initiated by activation of tyrosine kinases. Several cytokines including IL-2, IL-3, IL-4, IL-5, IL-6, and granulocyte-macrophage/colony-stimulating factor activate intracellular tyrosine kinases (11). Recently, the ras-encoded protein has been shown to act downstream of several tyrosine kinases (12)(13)(14). However, signaling events subsequent to ras are still poorly understood except that they involve the activation of several serine/threonine kinases. In the case of the IL-6 signaling process, IL-6-triggered association of IL-6 receptor and gpl3O activates ras in addition to an as yet unidentified tyrosine kinase (14)(15)(16)(17). Recently, gpl3O has been shown to be a common signal transducer for several cytokines, including IL-6, oncostatin M, leukemia inhibitory factor, and ciliary neurotrophic factor, suggesting that NF-IL6 may be the target of a common signal transduction pathway shared by several cytokines (18)(19)(20).As a first step toward understanding the gp130-mediated signaling pathway, we examined the effect of p21ras expression on NF-IL6-mediated transactivation and observed that coexpression of oncogenic p21ras stimulated the transcriptional activity of NF-IL6. Furthermore, we demonstrated that the ras-dependent activation of NF-IL6 was mediated through phosphorylation by mitogen-activated protein (MAP) kinases. §To whom reprint requests should be addressed. MATERIALS AND METHODS 2207The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with...

BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo

“…Several transcription factors, such as Elk-1 (Gille et al, 1992;Marais et al, 1993), c-Myc , c-Jun Pulverer et al, 1991), c-Fos (O®r et al, 1990), NF-IL-6 (Nakajima et al, 1993), TAL-1 (Cheng et al, 1993) and AML-1 (Tanaka et al, 1996) have been proposed to be substrates for MAPK in vitro. Furthermore, it has been reported that Elk-1 (Rao and Reddy, 1994), c-Myc (Gupta and Davis, 1994) and AML-1 (Tanaka et al, 1996) can associate with MAPK in vitro, whereas AP-1 can associate with MAPK in vivo (Bernstein et al, 1994).…”

Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction

“…The activation of p21ras signal transduction by a plethora of stimuli can lead to the phosphorylation of a number of transcription factors. These include: c-Jun (Binetruy et al, 1991;Pulverer et al, 1991), p62 TCF /Elk-1 (Marais et al, 1993), c-ets-1 (Co er et al, 1993;Galang et al, 1994;Giovane et al, 1994), NF-IL6 (Nakajima et al, 1993), c-Fos and c-Myc (Seth et al, 1992).…”

CCAAT Enhancer Binding Protein-β Regulates Matrix Metalloproteinase-1 Expression in Interleukin-1β–Stimulated A549 Lung Carcinoma Cells

“…It has been reported that phosphorylation of CEBPB on Thr 235 by ERK promotes the transcriptional activity of this transcription factor (14). Therefore, we assayed phosphorylation of the ERK-dependent site at Thr 235 of CEBPB in IL-1β-stimulated A549 cells.…”

“…CEBPB3 (liver-enriched inhibitory protein; LIP) is 148 amino acids in length, and has been reported to function as a transcriptional repressor due to its lack of a transactivation domain (13). CEBPB becomes transcriptionally active when phosphorylated on Thr 235 (Thr 217 in the mouse) by the ERK2-stimulated kinase known as p90 ribosomal S kinase (14).…”