Novel Protein Kinase C Isoforms Regulate Human Keratinocyte Differentiation by Activating a p38δ Mitogen-activated Protein Kinase Cascade That Targets CCAAT/Enhancer-binding Protein α

Efimova, Tatiana; Deucher, Anne; Kuroki, Toshio; Ohba, Masaaki; Eckert, Richard L.

doi:10.1074/jbc.m205098200

Cited by 88 publications

(121 citation statements)

References 51 publications

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“…PKCy has been recently reported to increase the phosphorylation of p38 in various cell types (17,47). However, the role of the subcellular localization of PKCy in this effect was not reported.…”

Section: Discussionmentioning

confidence: 79%

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

Gomel

Xiang

Finniss

et al. 2007

Molecular Cancer Research

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Protein kinase CD (PKCD) regulates cell apoptosis and survival in diverse cellular systems. PKCD translocates to different subcellular sites in response to apoptotic stimuli; however, the role of its subcellular localization in its proapoptotic and antiapoptotic functions is just beginning to be understood. Here, we used a PKCD constitutively active mutant targeted to the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) and examined whether the subcellular localization of PKCD affects its apoptotic and survival functions. PKCD-Cyto, PKCD-Mito, and PKCD-Nuc induced cell apoptosis, whereas no apoptosis was observed with the PKCD-ER. PKCD-Cyto and PKCD-Mito underwent cleavage, whereas no cleavage was observed in the PKCD-Nuc and PKCD-ER. Similarly, caspase-3 activity was increased in cells overexpressing PKCD-Cyto and PKCD-Mito. In contrast to the apoptotic effects of the PKCD-Cyto, PKCD-Mito, and PKCD-Nuc, the PKCD-ER protected the cells from tumor necrosis factor -related apoptosis-inducing ligand -induced and etoposideinduced apoptosis. Moreover, overexpression of a PKCD kinase-dead mutant targeted to the ER abrogated the protective effect of the endogenous PKCD and increased tumor necrosis factor -related apoptosis-inducing ligand -induced apoptosis. The localization of PKCD differentially affected the activation of downstream signaling pathways. PKCD-Cyto increased the phosphorylation of p38 and decreased the phosphorylation of AKT and the expression of X-linked inhibitor of apoptosis protein, whereas PKCD-Nuc increased c-Jun NH 2 -terminal kinase phosphorylation. Moreover, p38 phosphorylation and the decrease in X-linked inhibitor of apoptosis protein expression played a role in the apoptotic effect of PKCD-Cyto, whereas c-Jun NH 2 -terminal kinase activation mediated the apoptotic effect of PKCD-Nuc. Our results indicate that the subcellular localization of PKCD plays important roles in its proapoptotic and antiapoptotic functions and in the activation of downstream signaling pathways.

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Section: Discussionmentioning

confidence: 79%

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

Gomel

Xiang

Finniss

et al. 2007

Molecular Cancer Research

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“…This pathway promotes expression of the differentiation markers involucrin and transglutaminase 1 (Ohba et al, 1998;Cabodi et al, 2000;Kashiwagi et al, 2000). In these cells, TPA treatment leads to p38 activation observed by 2 h. Maximum p38 activity is maintained between 6 and 24 h post-TPA (Efimova et al, 2002). E2F1 levels begin to decrease 2-4 h after TPA treatment, and reach their minimum by 10 h. Importantly, the kinetics of E2F1 loss suggest that this event occurs just downstream from or in association with p38 activation.…”

Section: Discussionmentioning

confidence: 89%

E2F1 stability is regulated by a novel-PKC/p38β MAP kinase signaling pathway during keratinocyte differentiation

2005

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E2F transcription factors regulate proliferation, differentiation, DNA repair and apoptosis. Tight E2F regulation is crucial for epidermal formation and regeneration. However, virtually nothing is known about the molecular events modulating E2F during epidermal keratinocyte differentiation. Elucidation of these events is essential to understand epidermal morphogenesis, transformation and repair. Here we show that, in differentiating keratinocytes, Ca 2 þ -induced protein kinase C (PKC) activation downregulates E2F1 protein levels. Further, we have identified PKC d and g as those isoforms specifically involved in induction of E2F1 proteasomal degradation. We also demonstrate that E2F1 downregulation by novel PKC isozymes requires activation of p38b mitogenactivated protein kinase (MAPK). This is the first example of regulation in the E2F transcription factor family by activation of PKC and MAPK in the context of biologically significant differentiation stimuli in epithelia.

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“…As noted above, involucrin expression is controlled by a novel protein kinase c (nPKC), Ras, MEKK1, MEK3 signaling cascade which ultimately acts to increase AP1 factor level and binding to the hINV promoter AP1-1 site to activate hINV gene expression (Efimova and Eckert, 2000;Efimova et al, 1998;Efimova et al, 2002;Efimova et al, 2003;Efimova et al, 2004;Eckert et al, 2004;Welter et al, 1995). Our studies indicate that EGCG activates this pathway to increase hINV gene expression, and that this response can be inhibited using BIS-IM, an agent that inhibits all PKC isoforms (Balasubramanian et al, 2002).…”

Section: Differential Regulation Of Novel Protein Kinase Cmentioning

confidence: 99%

“…Keratinocyte differentiating agents, including calcium and phorbol ester, activate involucrin gene expression Efimova et al, 2002;Efimova et al, 2003) via a signaling cascade that includes the novel PKC isoforms (nPKC), Ras, MEKK1, and MEK3 (Agarwal et al, 1999;Welter et al, 1995;Efimova and Eckert, 2000;Efimova et al, 1998). Activation of this cascade leads to an increase in p38δ and a decrease in ERK1/2 activity leading to an increase in the levels of AP1, Sp1 and CAATT enhancer binding protein (C/EBP) expression, increased binding of these factors to the hINV promoter, and increased hINV gene expression (Banks et al, 1998;Welter et al, 1995;Crish et al, 2002).…”

mentioning

confidence: 99%

“…Activation of this cascade leads to an increase in p38δ and a decrease in ERK1/2 activity leading to an increase in the levels of AP1, Sp1 and CAATT enhancer binding protein (C/EBP) expression, increased binding of these factors to the hINV promoter, and increased hINV gene expression (Banks et al, 1998;Welter et al, 1995;Crish et al, 2002). Evidence for this cascade is provided by studies using pharmacological agents, constitutively-active and dominant-negative kinases, and kinase assays (Efimova and Eckert, 2000;Efimova et al, 1998;Efimova et al, 2002;Efimova et al, 2003). As a model to study the impact of dietary agents on keratinocyte function, we have studied the impact of a range of antioxidants on expression of involucrin (Crish et al, 1993;Crish et al, 1998;Crish et al, 2002;Eckert et al, 2004).…”

mentioning

confidence: 99%

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Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

Balasubramanian

Eckert

2007

Toxicology and Applied Pharmacology

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We have proposed that it is important to examine the impact of chemopreventive agents on the function of normal human epidermal keratinocytes, since these cells comprise the barrier that protects the body from a range of environmental insults. In this context, it is widely appreciated that cancer may be retarded by consumption or topical application of naturally-occurring food-derived chemopreventive agents. Our studies show that (−)-epigallocatechin-3-gallate (EGCG), a green teaderived polyphenol, acts to enhance the differentiation of normal human keratinocytes as evidenced by its ability to increase involucrin (hINV), transglutaminase type 1 (TG1) and caspase-14 gene expression. EGCG also stimulates keratinocyte morphological differentiation. These actions of EGCG are mediated via activation of a nPKC, Ras, MEKK1, MEK3, p38δ-ERK1/2 signaling cascade which leads to increased activator protein 1 (AP1) and CAATT enhancer binding protein (C/EBP) transcription factor expression, increased binding of these factors to DNA, and increased gene transcription. In contrast, apigenin, a dietary flavonoid derived from plants and vegetables, and curcumin, an agent derived from turmeric, inhibit differentiation by suppressing MAPK signal transduction and reducing API transcription factor level. Curcumin also acts to enhance apoptosis, although EGCG and apigenin do not stimulate apoptosis. In addition, all of these agents inhibit keratinocyte proliferation. These findings indicate that each of these diet-derived chemopreventive agents has a profound impact on normal human keratinocyte function and that they operate via distinct and sometimes opposing mechanisms. However, all are expected to act as chemopreventive agents. KeywordsEGCG; apigenin; curcumin; TPA; epidermis; involucrin; keratinocyte differentiation; apoptosis; chemoprevention; turmeric Keratinocyte differentiation and human involucrin gene expressionThe keratinocyte is the major cell type of the multilayered stratified squamous epithelium (the epidermis) that covers the body surface. To establish epidermal structure, keratinocytes in the basal layer undergo periodic cell division which gives rise to daughter cells that differentiate

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Novel Protein Kinase C Isoforms Regulate Human Keratinocyte Differentiation by Activating a p38δ Mitogen-activated Protein Kinase Cascade That Targets CCAAT/Enhancer-binding Protein α

Cited by 88 publications

References 51 publications

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

The Localization of Protein Kinase Cδ in Different Subcellular Sites Affects Its Proapoptotic and Antiapoptotic Functions and the Activation of Distinct Downstream Signaling Pathways

E2F1 stability is regulated by a novel-PKC/p38β MAP kinase signaling pathway during keratinocyte differentiation

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

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