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)

Epidermal keratinocyte differentiation is a tightly regulated, stepwise process that requires protein kinase C (PKC) activation. Studies using cultured mouse keratinocytes induced to differentiate with Ca2+ have indirectly implicated the alpha isoform of PKC in upregulation of "late" (granular cell) epidermal differentiation markers. Activation of this isoform is also implicated in the suppression of "early" differentiation markers keratin (K) 1 and 10 that characterizes the neoplastic phenotype produced by the v-Ha-ras oncogene. We used antisense oligonucleotides (AS) to directly address the role of PKC alpha in regulating expression of these markers in normal and v-Ha-ras-transduced primary keratinocytes and a keratinocyte cell line (SP-1) containing an activating mutation of the c-Ha-ras gene. Transfection of PKC alpha AS reduced the PKC alpha protein level in a dose-dependent manner, with a maximum effect at doses of 100 nM or higher. Immunoblot analysis with antibodies against PKC alpha, PKC delta, PKC epsilon, and PKC eta confirmed that PKC alpha AS selectively reduced the level of PKC alpha but not the other isoforms. In vitro kinase assays also revealed suppression of Ca(2+)-dependent PKC activity, which is the PKC alpha activity in this cell type, after transfection of PKC alpha AS. When PKC alpha AS-treated normal keratinocytes were stimulated to terminally differentiate with Ca2+, induction of the late differentiation markers loricrin, filaggrin, and SPR-1, as well as transglutaminase K mRNA, was suppressed when compared with their induction in scrambled AS-treated controls. In neoplastic v-Ha-ras-transduced keratinocytes and SP-1 cells, transfection of PKC alpha AS, but not the scrambled AS control, selectively downregulated PKC alpha and restored differentiation-specific expression of K1. These findings directly confirm that PKC alpha is an important component of the signaling pathway regulating terminal differentiation of normal keratinocytes and that activation of PKC alpha contributes to the altered differentiation program of neoplastic murine keratinocytes.
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PMID:Definition by specific antisense oligonucleotides of a role for protein kinase C alpha in expression of differentiation markers in normal and neoplastic mouse epidermal keratinocytes. 902 12

Tumour necrosis factor-alpha (TNF-alpha) deficient mice (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM-CSF, MMP-9 and MMP-3, was suppressed in TNF-alpha(-/-) compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-alpha(-/-) compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKC alpha, was also differentially regulated in wild-type compared with TNF-alpha(-/-) epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKC alpha was observed in TNF-alpha(-/-) epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-alpha(-/-) epidermis after DMBA treatment, suggesting that TNF-alpha was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical mediator of tumour promotion, acting via a PKC alpha- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.
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PMID:Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway. 1210 11

1,2-diacylglycerol (1,2-DAG) is involved in cell proliferation as an activator of protein kinase C (PKC) and has been shown to stimulate growth of cancer cells, raising the possibility of a role in tumor promotion. Ingested DAG oil, containing 70% 1,3-DAG and 30% 1,2-DAG, is digested and considered to be safe as edible oil. However, DAG may directly contact with oral cavity mucosa in undigested form. The present study was conducted to examine the effects of DAG oil on carcinogenesis in c-Ha-ras proto-oncogene transgenic (Tg) rats administered 4-nitroquinoline 1-oxide (4NQO, 10 ppm) in their drinking water for 10 weeks for initiation of mainly upper digestive organs. DAG oil added in basal diet at 5.5%, 2.75%, 1.38% and 0% with total fat made up to 5.5% with triacylglycerol (TAG) was administered during the initiation and post-initiation period. The study was terminated at week 12 (Tg females) and 20 (Tg males, wild females and males). The fatty acid composition of DAG oil was similar to TAG (linoleic acid 46.6% and oleic acid 38.9%). In Tg male rats, DAG oil administration was associated with significant increase (P<0.05) in the incidence of squamous cell carcinomas (SCC) of the tongue (5.5% DAG, 43.8%; 2.75% DAG, 20%; 1.38% DAG, 14.3%; 0%, 12.3%) with the Cochran-Armitage trend test and also number of tumors in coefficients for linear contrast trend tests. Tongue SCC induction of wild males and all females was not significant. The present results suggest that DAG oil may have enhancing and/or promotion potential for tongue carcinogenesis in male Tg featuring elevated ras expression.
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PMID:Possible enhancing activity of diacylglycerol on 4-nitroquinoline 1-oxide induced carcinogenesis of the tongue in human c-Ha-ras proto-oncogene transgenic rats. 1725 75

Pyrroloquinoline quinone (PQQ) has been implicated in certain physiological activities in mammals such as functioning as a potent growth factor in mice, and promoting DNA synthesis in human fibroblasts. These are clearly important physiological functions, however, the molecular mechanisms involved in PQQ activity are not yet fully understood. In order to address this, in this study we analyzed the effects of PQQ on the proliferation of NIH3T3 mouse fibroblasts and on their intracellular signal transduction mechanism. When activated c-Ha-ras-transformed NIH3T3 cells were treated with PQQ in the presence of 0.5% calf serum in DMEM, the cells showed significantly increased viability. After PQQ addition, flow cytometric analysis revealed a decrease in the population of cells in the G0/G1 phase and a concomitant increase in cells in the S and G2/M phases. Although treatment with SNAP, an NO donor, reduced cell viability, this effect was abolished by the addition of PQQ. Activation of ERK and PKC-epsilon was detected immediately after the addition of PQQ, and subsequent increases in the phosphorylation of Rb and c-Jun were observed. On the other hand, protein expression levels of growth-inhibitory molecules such as IkappaB and p27 decreased after PQQ treatment. These results suggest that PQQ stimulates cell proliferation through NO-sensitive Ras-mediated signaling pathways.
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PMID:Activation of Ras signaling pathways by pyrroloquinoline quinone in NIH3T3 mouse fibroblasts. 1739 81


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