Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors

Hirano, Toshio; Ishihara, Katsuhiko; Hibi, Masahiko

doi:10.1038/sj.onc.1203551

Cited by 1,082 publications

(852 citation statements)

References 159 publications

(156 reference statements)

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“…STAT3 is constitutively phosphorylated and activated in various primary human tumors and transformed cell lines, and has been implicated in tumorigenesis [2,3,4]. However, the molecular mechanisms of the persistent activation of STAT3 in human tumor cells remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…STAT3 was originally cloned as an acute-phase response factor activated by interleukin (IL)-6 in the mouse liver, and by its homology to STAT1 [1,2]. Growth factors, such as epidermal growth factor, platelet-derived growth factor and colony-stimulating factor-1, can also stimulate STAT3 activity [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…Growth factors, such as epidermal growth factor, platelet-derived growth factor and colony-stimulating factor-1, can also stimulate STAT3 activity [1,2]. The transcriptional factor plays crucial roles in early embryonic development as well as in other biological responses, including cell growth and apoptosis [1,2,3].…”

Section: Introductionmentioning

confidence: 99%

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Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Muromoto

Ikeda

Okabe

et al. 2009

Biochemical and Biophysical Research Communications

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The Epstein-Barr virus (EBV)-encoded latency protein EBNA2 is a nuclear transcriptional activator that is essential for EBV-induced cellular transformation. Here, we show that EBNA2 interacts with STAT3, a signal transducer for an interleukin-6 family cytokine, and enhances the transcriptional activity of STAT3 by influencing its DNA-binding activity. Furthermore, EBNA2 cooperatively acts on STAT3 activation with LMP1. These data demonstrate that EBNA2 acts as a transcriptional coactivator of STAT3.3

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Muromoto

Ikeda

Okabe

et al. 2009

Biochemical and Biophysical Research Communications

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“…In addition, VEGF induces activation of STAT3 and promotes its autocrine expression in RECs (Bartoli et al, 2000;Bartoli et al, 2003). Of interest, STAT3 activation is stimulated by inflammatory pathways (Hirano et al, 2000). Importantly, STAT3 has been shown to play a critical role in the process of HIF-1α activation and VEGF expression in multiple growth signaling pathways (Xu et al, 2005).…”

Section: Transcriptional Regulation Of Vegf Expression-tissuementioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Interleukin-6 is produced by MM cells and promotes myeloma cell proliferation in an autocrine manner (Klein et al, 1995;Chauhan et al, 1996;Jemal et al, 2003;Anderson, 2004) through phosphorylation of the signalling protein STAT3 (Kaptein et al, 1996;Hirano et al, 2000;Chatterjee et al, 2002). As Atiprimod inhibits NF-kB activity and, by doing so, suppresses IL-6 production, we wondered whether Atiprimod downregulates STAT3 phosphorylation.…”

Section: Atiprimod Downregulates Both Il-6-induced and Constitutive Smentioning

confidence: 99%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod 5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a timeand dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G 0 /G 1 phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X L , and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

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Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors

Cited by 1,082 publications

References 159 publications

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Epstein–Barr virus-derived EBNA2 regulates STAT3 activation

Vascular endothelial growth factor in eye disease

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

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