AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation

Rorke, Ellen A.; Adhikary, Gautam; Jans, Ralph; Crish, James F.; Eckert, Richard L.

doi:10.1038/onc.2010.315

Cited by 29 publications

(68 citation statements)

References 57 publications

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“…The transcription factors include AP1, CCAAT enhancer-binding protein, and Sp1, which move to the nucleus and bind to specific sites on the involucrin promoter to activate expression (48,(67)(68)(69)(70)(71). This molecular mechanism has been confirmed using transgenic mouse models (72)(73)(74)(75)(76).…”

Section: Discussionmentioning

confidence: 69%

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

Chew

Adhikary

Wilson

et al. 2011

Journal of Biological Chemistry

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PKC␦ increases keratinocyte differentiation and suppresses keratinocyte proliferation and survival. However, the mechanism of proliferation suppression is not well understood. The present studies show that PKC␦ overexpression increases p21Cip1 mRNA and protein level and promoter activity and that treatment with dominant-negative PKC␦, PKC␦-siRNA, or rottlerin inhibits promoter activation. Analysis of the p21Cip1 promoter upstream regulatory region reveals three DNA segments that mediate PKC␦-dependent promoter activation. The PKC␦ response element most proximal to the transcription start site encodes six GC-rich DNA elements. Mutation of these sites results in a loss of PKC␦-dependent promoter activation. Gel mobility supershift and chromatin immunoprecipitation reveal that these DNA elements bind the Kruppel-like transcription factor KLF4. PKC␦ increases KLF4 mRNA and protein level and KLF4 binding to the GC-rich elements in the p21 Cip1 proximal promoter. In addition, KLF4-siRNA inhibits PKC␦-dependent p21 Cip1 promoter activity. PKC␦ increases KLF4 expression leading to enhanced KLF4 interaction with the GC-rich elements in the p21 Cip1 promoter to activate transcription.PKC isoforms include three subfamilies of kinases that play a central role in the regulation of cell growth and differentiation (1). Classical PKCs (␣, ␤, and ␥) are calcium-, phospholipid-, and diacylglycerol-dependent; novel PKCs (nPKC ␦, ⑀, , and ) 2 are activated by diacylglycerol and phospholipids, but they do not respond directly to calcium; and atypical PKCs ( and ) are calcium-and diacylglycerol-independent but undergo allosteric activation (2, 3). Epidermal keratinocytes express PKC␣, ␤II, ␦, ⑀, , and (4 -10). These kinases have been studied in cultured keratinocytes and in animal models (11)(12)(13)(14)(15)(16)(17)(18)(19). A number of laboratories have shown that nPKC isoforms stimulate keratinocyte differentiation (15, 20 -24, 26). Consistent with this role, studies from our group show that the novel PKC (nPKC) isoforms stimulate keratinocyte differentiation by activating MAPK signaling, which results in increased nuclear levels of AP1, CCAAT enhancer-binding protein, and Sp1 transcription factors and binding of these factors to target genes to increase transcription (27)(28)(29). Involucrin is a classical marker of differentiation, and our studies show that PKC␦ is a potent activator of involucrin expression (21, 27, 30 -32).PKC isoforms have also been implicated in the regulation of keratinocyte proliferation (13,20,23,(33)(34)(35). This role is particularly important, because keratinocyte differentiation is associated with cessation of proliferation, and it would make mechanistic sense to have a common kinase activate both processes. A limited number of studies have examined the mechanism of nPKC regulation of keratinocyte proliferation. For example, the nPKC isoform PKC⑀ binds to and activates Fyn, a Src kinase, and this is associated with reduced keratinocyte proliferation (36). PKC⑀ forms a complex with cyclin E-cdk2-p21Cip1...

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Section: Discussionmentioning

confidence: 69%

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

Chew

Adhikary

Wilson

et al. 2011

Journal of Biological Chemistry

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“…In the course of studies designed to understand AP1 transcription factor function in epidermis, we produced mice in which AP1 transcription factor function is inactivated in the suprabasal epidermis (Rorke et al , 2010). In this model, we induce suprabasal epidermal expression of TAM67, a dominant-negative form of c-jun which inhibits AP1 factor function, using a doxycycline-inducible system.…”

Section: Discussionmentioning

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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“…1C). C-Jun is the most extensively studied protein of AP-1 components and has also been reported to be involved in the regulation of numerous cell activities, such as proliferation, survival, tumorigenesis and apoptosis (24–25). The transcriptional activation of c-Jun depends on its phosphorylation at Ser 63 and 73 in the transactivation domain (8–9, 11).…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies have strongly indicated that Chel A treatment leads to p53 protein accumulation and activation by preventing p53 proteins from degradation (4). c-Jun is a key member of the activator protein-1 (AP-1) family of transcription factors which bind to AP-1 elements in their target genes (37), and c-Jun/AP-1 activation is involved in the regulation of numerous cell biological activities, such as proliferation, survival, tumorigenesis and apoptosis (24–25). c-Jun appears to be both a positive and a negative regulator of apoptosis (37).…”

Section: Discussionmentioning

confidence: 99%

Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation

Zhu¹,

Zhang

Huang³

et al. 2014

Cancer Prevention Research

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Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the present study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP down-regulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A.

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AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation

Cited by 29 publications

References 57 publications

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

Protein Kinase C (PKC) δ Suppresses Keratinocyte Proliferation by Increasing p21Cip1 Level by a KLF4 Transcription Factor-dependent Mechanism

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

Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation

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