AP-1: a double-edged sword in tumorigenesis

Eferl, Robert; Wagner, Erwin F.

doi:10.1038/nrc1209

Cited by 1,892 publications

(1,912 citation statements)

References 77 publications

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“…Moreover, FRA1 protein stability induced by co‐treatment with UVB and CHX was decreased by naringenin or U0126. Others also reported that treatment with an RSK inhibitor, fmk, reduced FRA1 protein levels by 60%, whereas its transcription was unaffected 8, 10. This evidence and our results indicate that naringenin mediates FRA1 stability by inhibiting phosphorylation at Ser265, subsequently affecting AP‐1 and MMP‐1 expression.…”

Section: Discussionsupporting

confidence: 85%

“…Fos‐related antigen 1 plays an important role in the formation of AP‐1 complexes, which regulate the expression of specific genes such as MMP‐1 8, 10. Protein stability is a major regulatory outcome of FRA1 protein expression, and extracellular signal‐regulated kinase (ERK)1/2 signalling is an important mediator of FRA1 protein stability 7.…”

Section: Introductionmentioning

confidence: 99%

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Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Jung

et al. 2016

J Cellular Molecular Medi

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A number of natural phytochemicals have anti‐photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase‐1 (MMP‐1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB‐induced MMP‐1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3‐dimensional (3‐D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB. The mechanism and target(s) of naringenin were analysed by kinase assay and multiplex molecular assays. Dorsal skins of hairless mice were exposed to UVB 3 times per week, with a dose of irradiation that was increased weekly by 1 minimal erythema dose (MED; 45 mJ/cm2) to 4 MED over 15 weeks. Wrinkle formation, water loss and water content were then assessed. Naringenin suppressed UVB‐induced MMP‐1 expression and AP‐1 activity, and strongly suppressed UVB‐induced phosphorylation of Fos‐related antigen (FRA)‐1 at Ser265. Importantly, UVB irradiation‐induced FRA1 protein stability was reduced by treatment with naringenin, as well as with a mitogen‐activated protein kinase (MEK) inhibitor. Naringenin significantly suppressed UVB‐induced extracellular signal‐regulated kinase 2 (ERK2) activity and subsequently attenuated UVB‐induced phosphorylation of p90RSK by competitively binding with ATP. Constitutively active MEK (CA‐MEK) increased FRA1 phosphorylation and expression and also induced MMP‐1 expression, whereas dominant‐negative ERK2 (DN‐ERK2) had opposite effects. U0126, a MEK inhibitor, also decreased FRA1 phosphorylation and expression as well as MMP‐1 expression. The photoaging data obtained from mice clearly demonstrated that naringenin significantly inhibited UVB‐induced wrinkle formation, trans‐epidermal water loss and MMP‐13 expression. Naringenin exerts potent anti‐photoaging effects by suppressing ERK2 activity and decreasing FRA1 stability, followed by down‐regulation of AP‐1 transactivation and MMP‐1 expression.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Jung

et al. 2016

J Cellular Molecular Medi

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“…A well-known group of substrates of JNK is the AP-1 transcript factors that include Fos and Jun family members (Eferl and Wagner, 2003). However, different JNKs might be required in regulating the same AP-1 gene under different conditions.…”

Section: Jnksmentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

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“…Activated JUN mediates the response to signaling caused by tumor promoters, stress, UV irradiation and wounding. It is important in tumorigenesis by influencing cell proliferation, survival, transformation and invasion (reviewed in Eferl and Wagner, 2003;Johnson and Nakamura, 2007;Maeda and Karin, 2003;Yates and Rayner, 2002;Zenz and Wagner, 2006). In mice the effects of loss of Jun or loss of Jun activation are highly dependent on cell type and tissue (reviewed in Jochum et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

et al. 2009

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Sustained Hedgehog (HH) signaling is implicated in basal cell carcinoma of the skin and other types of cancer. Here we show that GLI1 and GLI2, the main transcriptional activators of the HH pathway, directly regulate expression of the activator protein 1 (AP-1) family member JUN, a transcription factor controlling keratinocyte proliferation and skin homeostasis. Activation of the JUN promoter by GLI is dependent on a GLI-binding site and the AP-1 sites known to be involved in self-activation of JUN. Transcription of JUN is greatly enhanced in the presence of GLI and requires activated JUN protein.GLI2act is a more potent activator than GLI1 in these experiments and physical interaction with phosphorylated JUN was only detected for GLI2act. The synergistic effect of GLI and JUN extends to the activation of further GLI target genes as shown by shRNA-mediated knockdown of JUN in human keratinocytes. Some of these cooperatively activated genes are involved in cell-cycle progression, which is consistent with a significant reduction of the proliferative potential of GLI in the absence of JUN. These results suggest a novel connection between HH/GLI pathway activity and JUN, which may contribute to the oncogenic activity of HH/GLI signaling in skin.

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AP-1: a double-edged sword in tumorigenesis

Cited by 1,892 publications

References 77 publications

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

Naringenin targets ERK2 and suppresses UVB‐induced photoaging

MAPK signaling in inflammation-associated cancer development

Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes

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