Structural analysis of the sequence coding for an inducible 26‐kDa protein in human fibroblasts

Haegeman, Guy; Content, Jean; Volckaert, Guido; Derynck, Rik; Tavernier, Jan; Fiers, Walter

doi:10.1111/j.1432-1033.1986.tb09931.x

Cited by 315 publications

(109 citation statements)

References 32 publications

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“…It plays a major role in the primary immune reaction and also displays various functions in liver, hematopoiesis, and nervous systems (Haegeman et al, 1986;Hirano et al, 1986;Zilberstein et al, 1986;Sehgal et al, 1989;Van Snick, 1990;Hirano, 1994). The IL-6 receptor complex is composed of the ligand binding a subunit and the signal transducer gp130 (Yamasaki et al, 1988;Taga et al, 1989;Hibi et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK

et al. 1997

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Tec/Btk tyrosine kinases are members of a subgroup of Src tyrosine kinase family. They are reported to be activated in response to cytokines, such as IL-3 and IL-6. Janus kinases (JAKs) are known to associate with certain cytokine receptors, e.g. gp130, the signal transducing subunit of IL-6 receptor, and the common b chain of IL-3 receptor, which can be activated upon receptor dimerization in response to cytokines. Here we show the association between Jak1/Jak2 and Tec or Jak1 and Btk. Furthermore, Jak1 but not Jak2 induces tyrosine phosphorylation of Btk, but not Tec. These observations suggest that upon cytokine stimulation JAKs activate Tec/Btk or induce their dimerization resulting in endogenous tyrosine phosphorylation. Furthermore using a yeast two-hybrid system we have identi®ed the target molecules for Tec, the p85 and p55PIK subunits of PI-3 kinase, and Vav. Tec associated with Vav through its SH2 domain independently of its kinase activity. In contrast the p85 and p55PIK subunits of PI-3 kinase associated with the SH2-kinase domain of Tec, dependent on Tec kinase activity. Consistent with these, IL-6 or IL-3 induced the association between Tec and the p85 subunit of PI-3 kinase in mammalian cells. These ®ndings suggest that Tec tyrosine kinase links cytokine receptors to PI-3 kinase probably through JAKs.

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Section: Introductionmentioning

confidence: 99%

Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK

et al. 1997

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“…IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20).…”

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confidence: 99%

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs) 4 that can impose rapid degradation and restrict translation (1-3). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref. 5). Most recently it has been found to contribute to regulation of RNA 3Ј-end processing (6).KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (7,8). Ksrp Ϫ/Ϫ cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (9). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs. 10 -13). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (14, 15), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (10).IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (21) and IL-1 (22). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (23). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

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“…Indeed, the molecule that we now call interleukin-6 (IL-6) was originally referred to by such diverse names as interferon-/? * (Weissenbach et al, 1980;Zilberstein et al, 1986), 26K factor (Content et al, 1982;Haegeman et al, 1986), B-cell stimulatory factor 2 (Hirano et al, 1985), hybridoma growth factor (van Snick et al, 1986;Brakenhoff et al, 1987), plasmacytoma growth factor (Nordan et al, 1987), hepatocytestimulatory factor (Gauldie et al, 1987), a hematopoietic factor Reprint requests to: Dr. R.J. Simpson, Ludwig Institute for Cancer Research, PO Box 2008, Royal Melbourne Hospital, Victoria 3050, Australia; e-mail: simpson@licre.ludwig.edu.au.…”

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confidence: 99%

Interleukin‐6: Structure‐function relationships

et al. 1997

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Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

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Structural analysis of the sequence coding for an inducible 26‐kDa protein in human fibroblasts

Cited by 315 publications

References 32 publications

Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK

Tec tyrosine kinase links the cytokine receptors to PI-3 kinase probably through JAK

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Interleukin‐6: Structure‐function relationships

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