Suppression of AP1 Transcription Factor Function in Keratinocyte Suppresses Differentiation

Han, Bingshe; Rorke, Ellen A.; Adhikary, Gautam; Chew, Yap Ching; Xu, Wen; Eckert, Richard L.

doi:10.1371/journal.pone.0036941

Cited by 23 publications

(23 citation statements)

References 59 publications

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“…The transcription factor activator protein 1 proteins (AP-1), composed of jun and fos proteins that form homodimers (jun/jun) and heterodimers (jun/fos) that bind to AP-1 factor DNA binding sites, have been implicated in keratinocyte proliferation and differentiation. [30][31][32] Indeed, phosphorylated c-Jun is present in the nuclei of transitional cells in these studies. Interestingly it has been reported that c-fos is sequestered in the nuclear envelope in a Lamin A/Cdependent manner, which effectively reduces AP-1 factor DNA binding activity.…”

Section: Discussionmentioning

confidence: 48%

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

Naeem¹,

Zhu²,

Di³

et al. 2015

Cell Death Differ

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Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, notably in atopic dermatitis and psoriasis. Keratinocyte nuclear degradation is not well characterised, and it is unclear whether the retained nuclei contribute to the altered epidermal differentiation seen in eczema and psoriasis. Loss of AKT1 function strongly correlated with parakeratosis both in eczema samples and in organotypic culture models. Although levels of DNAses, including DNase1L2, were unchanged, proteomic analysis revealed an increase in Lamin A/C. AKT phosphorylates Lamin A/C, targeting it for degradation. Consistent with this, Lamin A/C degradation was inhibited and Lamin A/C was observed in the cornified layer of AKT1 knockdown organotypic cultures, surrounding retained nuclear material. Using AKT-phosphorylation-dead Lamin A constructs we show that the retention of nuclear material is sufficient to cause profound changes in epidermal terminal differentiation, specifically a reduction in Loricrin, Keratin 1, Keratin 10, and filaggrin expression. We show that preventing nuclear degradation upregulates BMP2 expression and SMAD1 signalling. Consistent with these data, we observe both parakeratosis and evidence of increased SMAD1 signalling in atopic dermatitis. We therefore present a model that, in the absence of AKT1-mediated Lamin A/C degradation, DNA degradation processes, such as those mediated by DNAse 1L2, are prevented, leading to parakeratosis and changes in epidermal differentiation. Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. [1][2][3] Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, but most notably in the epidermal barrierdefective diseases eczema and psoriasis. 4,5 Mechanisms of nuclear degradation in the epidermis have not yet been well characterised and it is not known whether the retained nuclei contribute to the altered epidermal differentiation programmes seen in these skin diseases. 6,7 It is surprising that, for such a critical component of epidermal terminal differentiation, relatively few molecular mechanisms inducing parakeratosis have been investigated. The caspase-14 knockout mouse develops parakeratotic plaques upon chemical barrier disruption 8 and has subtle defects in epidermal terminal differentiation, including filaggrin processing, 9 whereas the DNAse 1L2 knockout mouse showed constitutive nuclear retention in hair and nails, which led to structural abnormalities in the hair shaft. 10,11 Parakeratosis also occurs during wound healing. 12 Nuclei are retained in the scab of healing wounds, and this correlates with...

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Section: Discussionmentioning

confidence: 48%

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

Naeem¹,

Zhu²,

Di³

et al. 2015

Cell Death Differ

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“…TAM67 forms inactive heterodimers with other AP1 factors which interact with AP1 response elements in a normal manner but do not active transcription. This results in reduced expression of AP1 responsive genes (Han et al , 2012). As an initial step in characterization of the role of TAM67-FLAG in epidermis, we confirmed that TAM67-FLAG interacts with AP1 response elements and reduces expression of AP1 target genes.…”

Section: Resultsmentioning

confidence: 99%

Suppressing AP1 Factor Signaling in the Suprabasal Epidermis Produces a Keratoderma Phenotype

Rorke

Adhikary

Young

et al. 2015

Journal of Investigative Dermatology

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Keratodermas comprise a heterogeneous group of highly debilitating and painful disorders characterized by thickening of the skin with marked hyperkeratosis. Some of these diseases are caused by genetic mutation, while other forms are acquired in response to environmental factors. Our understanding of signaling changes that underlie these diseases is limited. In the present study we describe a keratoderma phenotype in mice in response to suprabasal epidermis-specific inhibition of activator protein 1 transcription factor signaling. These mice develop a severe phenotype characterized by hyperplasia, hyperkeratosis, parakeratosis and impaired epidermal barrier function. The skin is scaled, constricting bands encircle the tail and digits, the footpads are thickened and scaled, and loricrin staining is markedly reduced in the cornified layers and increased in the nucleus. Features of this phenotype, including nuclear loricrin localization and pseudoainhum (autoamputation), are characteristic of Vohwinkel Syndrome. We confirm that the phenotype develops in a loricrin null genetic background, indicating that suppressed suprabasal AP1 factor function is sufficient to drive this disease. We also show that the phenotype regresses when suprabasal AP1 factor signaling is restored. Our findings suggest that suppression of AP1 factor signaling in the suprabasal epidermis is a key event in the pathogenesis of keratoderma.

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“…In vitro , BACHs bind to AP1/NF-E2 binding sites, TGA(GC)TCA [28]. We note that transcriptionally functional AP1 sites have been found in a large proportion of keratinocyte differentiation marker genes [29-33]. The expression of the individual members of the AP1 protein family in different layers of the epidermis is controversial.…”

Section: Resultsmentioning

confidence: 99%

Profiling and metaanalysis of epidermal keratinocytes responses to epidermal growth factor

Blumenberg

2013

BMC Genomics

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BackgroundOne challenge of systems biology is the integration of new data into the preexisting, and then re-interpretation of the integrated data. Here we use readily available metaanalysis computational methods to integrate new data on the transcriptomic effects of EGF in primary human epidermal keratinocytes with preexisting transcriptomics data in keratinocytes and in EGF-treated non-epidermal cell types.ResultsWe find that EGF promotes keratinocyte proliferation, attachment and motility and, surprisingly, induces DUSPs that attenuate the EGF signal. Our metaanalysis identified overlapping effects of EGF with those of IL-1 and IFNγ, activators of keratinocyte in inflammation and wound healing. We also identified the genes and pathways suppressed by EGF but induced by agents promoting epidermal differentiation. Metaanalysis comparison with the EGF effects in other cell types identified extensive similarities between responses in keratinocytes and in other epithelial cell types, but specific differences with the EGF effects in endothelial cells, and in transformed, oncogenic epithelial cell lines.ConclusionsThis work defines the specific transcriptional effects of EGF on human epidermal keratinocytes. Our approach can serve as a suitable paradigm for integration of new omics data into preexisting databases and re-analysis of the integrated data sets.

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Suppression of AP1 Transcription Factor Function in Keratinocyte Suppresses Differentiation

Cited by 23 publications

References 59 publications

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

Suppressing AP1 Factor Signaling in the Suprabasal Epidermis Produces a Keratoderma Phenotype

Profiling and metaanalysis of epidermal keratinocytes responses to epidermal growth factor

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