Protein Kinase C Epsilon Signals Ultraviolet Light-induced Cutaneous Damage and Development of Squamous Cell Carcinoma Possibly Through Induction of Specific Cytokines in a Paracrine Mechanism¶

Wheeler, Deric L.; Li, Y.; Verma, Ajit Kumar

doi:10.1562/2004-08-12-ra-271.1

Cited by 25 publications

(23 citation statements)

References 37 publications

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“…PKC-d, PKC-Z) tumor formation (Reddig et al, 1999(Reddig et al, , 2000Jansen et al, 2001;Chida et al, 2003;Wheeler et al, 2003Wheeler et al, , 2004Wheeler et al, , 2005Papp et al, 2004). While there is selective loss of PKC-d in ras-transformed HaCaT cells, loss of PKC-e has been reported in both mouse and human SCCs (Wheeler et al, 2005), and thus multiple PKC isoform changes can occur during multi-step skin carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas

et al. 2005

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Section: Discussionmentioning

confidence: 99%

The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas

et al. 2005

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“…Taken together, accumulating data provide strong evidence that the activation of some TPA dependent PKCs, especially of PKC and PKC , and the deactivation of others, like PKC and PKC , is crucial for the induction of tumorigenesis and for tumor progression (EWmova et al 2002;Fagerstrom et al 1996;Shimao et al 1999;Wheeler et al 2005). In addition concerning tumor therapy, PKC for example could also mediate multidrug resistence as recently demonstrated in human leukemia cells and in some carcinoma cell lines (Gariboldi et al 2001(Gariboldi et al , 2003.…”

Section: Role Of Speciwc Pkc Isoforms In Skin Tumorigenesismentioning

confidence: 99%

Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium

Breitkreutz

Braiman-Wiksman²,

Daum

et al. 2007

J Cancer Res Clin Oncol

128

121

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The protein kinase C (PKC) family represents a large group of phospholipid dependent enzymes catalyzing the covalent transfer of phosphate from ATP to serine and threonine residues of proteins. Phosphorylation of the substrate proteins induces a conformational change resulting in modification of their functional properties. The PKC family consists of at least ten members, divided into three subgroups: classical PKCs (alpha, betaI, betaII, gamma), novel PKCs (delta, epsilon, eta, theta), and atypical PKCs (zeta, iota/lambda). The specific cofactor requirements, tissue distribution, and cellular compartmentalization suggest differential functions and fine tuning of specific signaling cascades for each isoform. Thus, specific stimuli can lead to differential responses via isoform specific PKC signaling regulated by their expression, localization, and phosphorylation status in particular biological settings. PKC isoforms are activated by a variety of extracellular signals and, in turn, modify the activities of cellular proteins including receptors, enzymes, cytoskeletal proteins, and transcription factors. Accordingly, the PKC family plays a central role in cellular signal processing. Accumulating data suggest that various PKC isoforms participate in the regulation of cell proliferation, differentiation, survival and death. These findings have enabled identification of abnormalities in PKC isoform function, as they occur in several cancers. Specifically, the initiation of squamous cell carcinoma formation and progression to the malignant phenotype was found to be associated with distinct changes in PKC expression, activation, distribution, and phosphorylation. These studies were recently further extended to transgenic and knockout animals, which allowed a more direct analysis of individual PKC functions. Accordingly, this review is focused on the involvement of PKC in physiology and pathology of the skin.

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“…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).…”

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confidence: 99%

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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Protein Kinase C Epsilon Signals Ultraviolet Light-induced Cutaneous Damage and Development of Squamous Cell Carcinoma Possibly Through Induction of Specific Cytokines in a Paracrine Mechanism¶

Cited by 25 publications

References 37 publications

The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas

The proapoptotic tumor suppressor protein kinase C-δ is lost in human squamous cell carcinomas

Protein kinase C family: On the crossroads of cell signaling in skin and tumor epithelium

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

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