Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The eta isoform of protein kinase C (PKC eta) is classified into the Ca2+-independent novel PKC subfamily and assigned to human chromosome 14 (14q22-23) and mouse chromosome 12 (12C3-D2). It is highly expressed in epithelial tissues especially in squamous epithelia. PKC eta is unique in that it is specifically activated by cholesterol sulfate and sulfatide, sulfated metabolites of cholesterol and cerebroside, respectively. PKC eta overexpression induces G1 arrest and differentiation in keratinocytes. PKC eta-induced differentiation is accompanied by the transcriptional activation of transglutaminase I, a key enzyme in squamous differentiation, and involucrin, a precursor of cornified envelopes. In keratinocytes, PKC eta associates with the cyclin E/cdk2/p21 complex and inhibits the cdk2-kinase activity, leading to G1 arrest. Cholesterol sulfate inhibits the promotional phase of skin carcinogenesis. Moreover, PKC eta-knockout mice show a much higher sensitivity to carcinogenesis, suggesting that PKC eta is negatively involved in tumor promotion through stimulation of keratinocyte differentiation. In addition to epithelial cells, recent studies revealed that PKC eta acts as a key regulator in early B-cell development. Although the functions of PKC eta in other cell types are not yet fully elucidated, available evidence indicates that this particular isoform plays crucial roles in the signaling of cell differentiation in a cell-type-specific manner.
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PMID:Protein kinase C eta (PKC eta): its involvement in keratinocyte differentiation. 1247 86

Calcium induces both involucrin and transglutaminase-K in normal keratinocytes (NHK) but not in squamous carcinoma cell lines (SCC). The protein kinase C (PKC) agonist phorbol myristoyl acetate potentiates and the PKC antagonist Ro31-8220 blocks the ability of calcium to stimulate the involucrin promoter in normal human keratinocytes but not in SCC4. We thus examined the ability of calcium to regulate the levels of five PKC isozymes in NHK and two SCC. In the normal keratinocytes, the levels of PKC [alpha], PKC [delta], PKC [eta], and PKC [zeta] increased over the first one to two weeks in a calcium-and time-dependent manner. PKC [epsilon] decreased in a time-and calcium-dependent fashion over the three-week period. All five isozymes showed little change during culture in SCC4 at any calcium concentration. Calcium and time of culture had partial effects on SCC12B2, a carcinoma that shows partial differentiation characteristics. Since PKC [alpha] is the only calcium responsive PKC isozyme in keratinocytes and most likely to be directly involved in calcium induced differentiation, we evaluated the effect of inhibiting its production with antisense oligonucleotides on calcium-regulated markers of differentiation. We found that the PKC [alpha] specific antisense oligonucleotide blocked calcium stimulated involucrin promoter activity as well as PKC [alpha], involucrin, and transglutaminase protein production, whereas the sense oligonucleotide control did not. We conclude that although a number of PKC isozymes are regulated during calcium-induced differentiation, PKC [alpha] plays a necessary role in mediating calcium-induced differentiation. Failure to regulate PKC [alpha] in SCC4 may underlie at least part of the failure of calcium to promote differentiation in these cells.
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PMID:Role of protein kinase C alpha in calcium induced keratinocyte differentiation: defective regulation in squamous cell carcinoma. 1265 52

Stratified squamous epithelial cells undergo an orderly process of terminal differentiation that is characterized by specific molecular and morphological changes, including expression of the cornified envelope protein involucrin. Significant progress has been made in characterizing the upstream regulatory region of the involucrin gene. Binding sites for AP-1 (activator protein 1) and Sp1 transcription factors were shown to be important for involucrin promoter activity and tissue-specific expression. Defective terminal differentiation is often characterized by decreased or lack of involucrin expression. Recently, a dominant-negative construct of the transcriptional co-activator P/CAF [p300/CBP-associated factor, where CBP stands for CREB (cAMP-response-element-binding protein)-binding protein] was shown to inhibit involucrin expression in immortalized keratinocytes [Kawabata, Kawahara, Kanekura, Araya, Daitoku, Hata, Miura, Fukamizu, Kanzaki, Maruyama and Nakajima (2002) J. Biol. Chem. 277, 8099-8105]. Loss of expression or inactivation of other co-activators has also been demonstrated [Suganuma, Kawabata, Ohshima, and Ikeda (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 13073-13078]. In the present study, we re-expressed CBP and P/CAF in immortalized keratinocyte lines that had lost expression of these co-activator proteins. Re-expression of these proteins restored calcium- and RA (retinoic acid)-responsive involucrin expression in these cells. RA and calcium signalling induced exchange of CBP and P/CAF occupancy at the AP-1 sites of the involucrin promoter. CBP and P/CAF inductions of the involucrin expression were not dependent on MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase), p38, protein kinase C or CaM kinase (calcium/calmodulin-dependent kinase) signalling. Kinase-induced changes in involucrin promoter activity directly resulted from changes in AP-1 protein expression. We concluded that CBP and P/CAF are important regulators of involucrin expression in stratified squamous epithelial cells.
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PMID:Regulation of the human involucrin gene promoter by co-activator proteins. 1502 63

The keratinization process in psoriasis is a unique phenomenon. We have proposed an organized system for keratinization in psoriasis based on the recognition of early and late differentiation markers combined with premature cell death. The early differentiation markers, such as involucrin, small proline-rich proteins (SPRR), cystatin A and transglutaminase l, are more conspicuously expressed in psoriasis, while the late differentiation markers, such as profilaggrin and loricrin, are abolished. Keratinization markers that are not observed in the normal epidermis are also detected; these include SKALP/elafin as well as K6 and K16. With a markedly diminished turnover time, the psoriatic epidermis rapidly synthesizes differentiation markers that are mostly under the control of the protein kinase C-AP1 transcriptional control system. Because of the premature cell death, however, the late differentiation markers are not expressed. During the improvement of the lesion and the therefore longer turnover time, the late differentiation markers rapidly catch up to reveal their expression. This explains the rapid appearance of keratohyalin granules (profilaggrin) in the healing lesion of psoriasis. Thus the keratinization process in psoriasis can be explained by the accelerated keratinization combined with premature cell death. The keratinization process in psoriasis is unique, because both accelerated keratinization and premature cell death co-exist, resulting in the disappearance of late differentiation markers such as profilaggrin and loricrin. It is interesting to note that the premature cell death is also under the control of protein kinase C signaling.
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PMID:Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death. 1518 21

The epidermis is a dynamic renewing structure that provides life-sustaining protection from the environment. The major cell type of the epidermis, the epidermal keratinocyte, undergoes a carefully choreographed program of differentiation. Alteration of these events results in a variety of debilitating and life-threatening diseases. Understanding how this process is regulated is an important current goal in biology. In this review, we summarize the literature regarding regulation of involucrin, an important marker gene that serves as a model for understanding the mechanisms that regulate the differentiation process. Current knowledge describing the role of transcription factors and signaling cascades in regulating involucrin gene expression are presented. These studies describe a signaling cascade that includes the novel protein kinase C isoforms, Ras, MEKK1, MEK3, and a p38delta-extracellular signal regulated kinase 1/2 complex. This cascade regulates activator protein one, Sp1, and CCATT/enhancer-binding protein transcription factor DNA binding to two discrete involucrin promoter regions, the distal- and proximal-regulatory regions, to regulate involucrin gene expression.
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PMID:Regulation of involucrin gene expression. 1519 37

Previously we documented that human epidermis exclusively expresses corticotropin releasing hormone receptor 1 (CRH-R1). To define the role of CRH in the epidermis, we investigated its effects on differentiation of normal human adult epidermal keratinocytes. Thus, CRH inhibited proliferation in a dose dependent fashion and significantly decreased Ki-67 antigen expression. This effect was independent of either the presence or the absence of growth factors in the medium. Flow cytometry analysis demonstrated that CRH inhibited the transition from G0/1 to S phase of the cell cycle, which was accompanied by an increased expression of cdk inhibitor p16 (Ink4a) protein. The antiproliferative effect was attenuated by protein kinase C inhibitor (GF109203X) but not by H89 (protein kinase A inhibitor), PD98059, or SB203580 (MAP kinase inhibitors). The cell cycle withdrawal was associated with the induction of keratinocyte differentiation. Thus, CRH stimulated the expression of cytokeratin 1 and involucrin, and inhibited cytokeratin 14 on both mRNA and protein levels. It also increased cell granularity and cell size. Furthermore, CRH induced signal transduction cascade that included stimulation of inositol 1,4,5-triphosphate, which was time and dose dependent. CRH also increased activator protein-1 DNA binding activity with JunD identified as the most important element. Thus, activation of CRH-R1 induces a non-random and sequential signal transduction cascade governing both keratinocyte differentiation and the inhibition of cell proliferation through G0/1 arrest. We propose that this program, triggered by CRH interaction with CRH-R1, includes induction of a transduction pathway involving the sequential activation of phospholipase C, protein kinase C, activator protein-1 (including Jun D), and p16.
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PMID:Corticotropin-releasing hormone induces keratinocyte differentiation in the adult human epidermis. 1546 47

IkappaB kinase (IKK) alpha and beta share the function to phosphorylate IkappaB to activate a transcription factor NF-kappaB. Recent reports, however, revealed differences in the functions of the two kinases. The present study was designed to determine a unique function of IKKalpha on the differentiation of squamous cell carcinoma (SCC). Transfection with IKKalpha gene, but neither IKKbeta nor NF-kappaB gene, inhibited the constitutive expressions as well as extracellular calcium-induced expressions of involucrin and filaggrin, epithelial differentiation markers, in cultured SCC cells. Morphological changes from polygonal to fibroblastic shape were seen in the SCC cells stably expressing green-fluorescent protein (GFP)-fused IKKalpha while intracellular localization of GFP-IKKalpha differed from that of GFP-IKKbeta. Interestingly, phorbol myristate acetate together with IKKalpha gene transfection strongly inhibited the expression of involucrin in SCC cells and induced the phosphorylation of serine residue in IKKalpha, suggesting that protein kinase C is involved in the effect of IKKalpha on the differentiation of SCC cells. In conclusion, high expression of IKKalpha may serve as an intracellular signal to halt the epithelial differentiation of SCC cells.
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PMID:Effects of IkappaB kinase alpha on the differentiation of squamous carcinoma cells. 1597 84

A group of potential differentiation-associated genes had been identified by microarray analysis as c-Jun/AP-1 target genes essential for epithelial differentiation program. Our previous study showed that c-Jun/AP-1 could bind and activate these gene promoters in vivo using chromatin immunoprecipitation. To further understand how the mitogen-activated protein kinase signaling pathways regulate AP-1 activity and expression of c-Jun target genes, our strategy was based on the use of 12-o-tetradecanoylophorbol-13-acetate (TPA) and pharmacological reagents to induce or block c-Jun expression. The mRNA and protein expression of these genes increased in response to TPA-induced c-Jun/AP-1 expression. Inhibitors of JNK (SP600125) and PKC (GF109203X) mainly blocked expression and phosphorylation of c-Jun, while inhibition of MEK-ERK activity with PD98059 (an inhibitor of MEK) had little effect. Expression of involucrin and keratin 4 in response to TPA was attenuated by pretreatments with GF109203X and SP600125, but not PD98059, suggesting involvement of PKC and JNK in this response. Taken together, these results suggested that differentiation-associated genes were regulated by TPA-induced c-Jun/AP-1 mainly via a PKC/JNK pathway in esophageal cancer cell line KYSE450.
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PMID:Differentiation-associated genes regulated by TPA-induced c-Jun expression via a PKC/JNK pathway in KYSE450 cells. 1648 Sep 52

Non-receptor tyrosine kinase proline-rich protein tyrosine kinase 2 (Pyk2) functions as an integrator of multiple signaling pathways involved in the regulation of fundamental cellular processes. Pyk2 expression, regulation, and functions in skin have not been examined. Here we investigated the expression and subcellular localization of Pyk2 in human epidermis and in primary human keratinocytes, and studied the mechanisms of Pyk2 activation by differentiation-inducing stimuli, and the role of Pyk2 as a regulator of keratinocyte differentiation. We demonstrate that Pyk2 is abundantly expressed in skin keratinocytes. Notably, the endogenous Pyk2 protein is predominantly localized in keratinocyte nuclei throughout all layers of healthy human epidermis, and in cultured human keratinocytes. Pyk2 is activated by treatment with keratinocyte-differentiating agents, 12-O-tetradecanoylphorbol-13-acetate and calcium via a mechanism that requires intracellular calcium release and functional protein kinase C (PKC) and Src activities. Particularly, differentiation-promoting PKC delta and PKC eta elicit Pyk2 activation. Our data show that Pyk2 increases promoter activity and endogenous protein levels of involucrin, a marker of keratinocyte terminal differentiation. This regulation is associated with increased expression of Fra-1 and JunD, activator protein-1 transcription factors known to be required for involucrin expression. Altogether, these results provide insights into Pyk2 signaling in epidermis and reveal a novel role for Pyk2 in regulation of keratinocyte differentiation.
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PMID:The role of proline-rich protein tyrosine kinase 2 in differentiation-dependent signaling in human epidermal keratinocytes. 1720 62

Normal human epidermal keratinocytes (NHEK) respond to the autocrine activated extracellular signal-regulated kinase (ERK) signaling pathway, which contributes to the survival of keratinocytes. However, during the condition of calcium-induced differentiation, how the autocrine ERK signaling is regulated and affected is poorly understood. The purpose of this study was to understand and to obtain clues to the possible function of the autocrine ERK activation during the calcium-induced differentiation of NHEK. We demonstrated that the autocrine activated ERK was not interrupted by calcium triggering and that it was sustained for at least one day after changing the medium. We also found that the autocrine ERK activation was associated with the expression of cyclin D1 and the cell cycle regulation at the early stage of calcium triggering by treating the cells with the mitogen-activated protein kinase inhibitor PD98059. However, the PD98059 treatment did not have a significant influence on the expression of involucrin and loricrin. In addition, we demonstrated that autocrine ERK activation was associated with protein kinase C and p38MAPK signaling. We suggest that the activation of autocrine ERK is not interrupted by calcium triggering and it might participate in cell growth during the early stage of calcium-induced differentiation in NHEK.
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PMID:Autocrine extracellular signal-regulated kinase activation in normal human keratinocytes is not interrupted by calcium triggering and is involved in the control of cell cycle at the early stage of calcium-induced differentiation. 1744 39


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