Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

Wang, Yanping; Ripperger, Juergen; Fey, Georg H.; Samols, David; Kordula, Tomek; Wetzler, Meir; Etten, Richard A. Van; Baumann, Heinz

doi:10.1002/hep.510300318

Cited by 55 publications

(52 citation statements)

References 86 publications

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“…The present results with the inhibitor CGP77675, suggested that c-Scr tyrosine kinase is selectively involved in the EGF-induced activation of Stat5b in hepatocytes. These findings obtained in normal cells are in agreement with results indicating a role of c-Src tyrosine kinase in the EGF receptor-mediated activation of Stat5 in A431 and HepG2 cells (Olayioye et al, 1999;Wang et al, 1999). We have observed that EGF induces tyrosine phosphorylation of paxillin, which may be a downstream response to c-Src (Missbach et al, 1999), and was sensitive to pharmacological inhibition of c-Src, and this effect was more pronounced in high-density cultures (data not shown).…”

Section: Discussionsupporting

confidence: 91%

“…Reports from hepatocytes and hepatocyte-related models have suggested that STAT proteins, including Stat5, are involved in functions associated with a high degree of cell differentiation (Runge et al, 1998;Wang et al, 1999), in analogy with the role of Stat5 in mammary gland development and lactogenesis (Miyoshi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Src has also been reported to activate Stat5 (Kazansky et al, 1999;Reddy et al, 2000), and recent findings in A431 and HepG2 cells suggest that c-Src may be involved in EGF receptor-mediated activation of Stat5 (Olayioye et al, 1999;Wang et al, 1999), while PDGF-induced Stat5 activation was independent of c-Src and c-Fyn in some transfected cells and cell-free systems (Paukku et al, 2000). To examine the role of c-Src in the effect of EGF on Stat5b activation in the cultured hepatocytes, we preincubated the cells for 90 min with CGP77675, an inhibitor of the c-Src kinase (Missbach et al, 1999;Susa et al, 2000), prior to stimulation with an agonist.…”

Section: Constitutive Serine Phosphorylation Of Stat5bmentioning

confidence: 98%

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EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

Guren

Ødegård

Abrahamsen

et al. 2003

Journal Cellular Physiology

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Signal transducer and activator of transcription (STAT) proteins may be activated by epidermal growth factor (EGF), but their role in EGF receptor-mediated mitogenic signaling is not clear. We previously showed that Stat5b was activated by EGF in rat hepatocytes in primary monolayer culture. In the present study, we found that EGF induced tyrosine phosphorylation of Stat5b both on Tyr-699, which correlated with specific DNA binding activity, and also on other tyrosine residues. The Src tyrosine kinase inhibitor CGP77675 blocked the EGF-induced activation of Stat5b, but did not affect the Stat5b activation by growth hormone (GH) or prolactin (PRL). The Stat5b response to EGF was most pronounced soon (3 h) after plating (early G 1 ) and at high cell density (50,000 hepatocytes per cm 2 ). However, at this cell density EGF did not stimulate DNA synthesis. In hepatocytes at 24 h of culturing (mid/late G 1 ) with 20,000 cells per cm 2 , EGF induced strong phosphorylation of the EGF receptor, as well as Shc and ERK, and stimulated DNA synthesis, but did not activate Stat5b, although the Stat5b response to GH or PRL was retained. A strong GHinduced Stat5b activation neither influenced the DNA synthesis alone nor enhanced the mitogenic effect of EGF. The results show that EGF induces tyrosine phosphorylation and DNA-binding activity of Stat5b in a manner different from GH and PRL, apparently by a Src-dependent mechanism. The data also provide further evidence that Stat5b is not required for mitogenic signaling from the EGF receptor.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Constitutive Serine Phosphorylation Of Stat5bmentioning

confidence: 98%

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EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

Guren

Ødegård

Abrahamsen

et al. 2003

Journal Cellular Physiology

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“…The ®ndings of our study and others highlight the signi®cance of cellular context in determining the biological functions of STAT3. In hepatic cells, the IL-6-mediated JAK/STAT3 pathway activation has been well known to be tightly linked to the regulation of many acute-phase protein (APP) genes (Zhang et al, 1999;Wang et al, 1999b;Andrejko et al, 1998), suggesting that the JAK/STAT3 pathway should be predominant in tissue in¯ammation. However, a minor role in cell survival is also suggested for STAT3, because blocking the STAT3 pathway could partly abolish the IL-6-mediated anti-apoptotic e ect (Chen et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6

et al. 2001

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“…The synthesis of CRP in hepatocytes is regulated at the transcriptional level (5,6). In hepatoma cells, IL-6 induces CRP expression by activating transcription factors STAT3 (7)(8)(9)(10) and C/EBP␤ (9,11). IL-1␤ synergistically enhances the effects of IL-6, in part through the activation of NF-B (12)(13)(14).…”

mentioning

confidence: 99%

A Novel RBP-Jκ-Dependent Switch from C/EBPβ to C/EBPζ at the C/EBP Binding Site on the C-Reactive Protein Promoter

Singh

Voleti

Agrawal

2007

The Journal of Immunology

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Regulation of basal and cytokine (IL-6 and IL-1β)-induced expression of C-reactive protein (CRP) in human hepatoma Hep3B cells occurs during transcription. A critical transcriptional regulatory element on the CRP promoter is a C/EBP binding site overlapping a NF-κB p50 binding site. In response to IL-6, C/EBPβ and p50 occupy the C/EBP-p50 site on the CRP promoter. The aim of this study was to identify the transcription factors occupying the C/EBP-p50 site in the absence of C/EBPβ. Accordingly, we treated Hep3B nuclear extract with a C/EBP-binding consensus oligonucleotide to generate an extract lacking active C/EBPβ. Such treated nuclei contain only C/EBPζ (also known as CHOP10 and GADD153) because the C/EBP-binding consensus oligonucleotide binds to all C/EBP family proteins except C/EBPζ. EMSA using this extract revealed formation of a C/EBPζ-containing complex at the C/EBP-p50 site on the CRP promoter. This complex also contained RBP-Jκ, a transcription factor known to interact with κB sites. RBP-Jκ was required for the formation of C/EBPζ-containing complex. The RBP-Jκ-dependent C/EBPζ-containing complexes were formed at the C/EBP-p50 site on the CRP promoter in the nuclei of primary human hepatocytes also. In luciferase transactivation assays, overexpressed C/EBPζ abolished both C/EBPβ-induced and (IL-6 + IL-1β)-induced CRP promoter-driven luciferase expression. These results indicate that under basal conditions, C/EBPζ occupies the C/EBP site, an action that requires RBP-Jκ. Under induced conditions, C/EBPζ is replaced by C/EBPβ and p50. We conclude that the switch between C/EBPβ and C/EBPζ participates in regulating CRP transcription. This process uses a novel phenomenon, that is, the incorporation of RBP-Jκ into C/EBPζ complexes solely to support the binding of C/EBPζ to the C/EBP site.

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Modulation of hepatic acute phase gene expression by epidermal growth factor and src protein tyrosine kinases in murine and human hepatic cells

Cited by 55 publications

References 86 publications

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

EGF receptor‐mediated, c‐Src‐dependent, activation of Stat5b is downregulated in mitogenically responsive hepatocytes

The involvement of PI 3-K/Akt-dependent up-regulation of Mcl-1 in the prevention of apoptosis of Hep3B cells by interleukin-6

A Novel RBP-Jκ-Dependent Switch from C/EBPβ to C/EBPζ at the C/EBP Binding Site on the C-Reactive Protein Promoter

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