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

Phorbol esters, which activate protein kinase C, stimulate the growth of normal human melanocytes yet inhibit the growth of most melanoma cells. We investigated whether apoptosis mediates the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on melanocyte and melanoma cell growth. Few apoptotic cells were present when melanocytes were cultured with TPA. Upon removal of TPA, the number of apoptotic cells increased over 10 days. Addition of TPA did not induce apoptosis in a metastatic melanoma cell line, Demel, although it strongly inhibited its growth. Protection of normal melanocytes from apoptosis was associated with high levels of Bcl-2. Following withdrawal of TPA from melanocytes, the expression of Bcl-2 decreased steadily. Bax and Bcl-X(L) levels did not differ between melanoma cells or melanocytes and were unaffected by the addition of TPA. These results suggest that TPA plays an important role in stimulating the growth of melanocytes by promoting anti-apoptotic mechanisms associated with high levels of Bcl-2.
Melanoma Res 2000 Oct
PMID:Survival mechanisms induced by 12-O-tetradecanoylphorbol-13-acetate in normal human melanocytes include inhibition of apoptosis and increased Bcl-2 expression. 1109 1

Transforming growth factor-beta (TGFbeta) contributes to the promotion of invasion, metastasis, angiogenesis and even immunosuppression. Since overexpression of the delta isoform of protein kinase C (nPKCdelta) in BL6 murine melanoma cells (BL6T cells) increases their metastatic capacity, we investigated the possible involvement of TGFbeta1 in this process. Immunohistochemical analysis demonstrated lower levels of TGFbeta1 in BL6T lung metastases compared with BL6 lung metastases. On the other hand, higher levels of this cytokine, in particular in its active form, occur in the plasma of BL6T metastasized animals, suggesting a nPKCdelta-dependent TGFbeta1 release. Therefore, nPKCdelta-dependent TGFbeta1 release and activation may be involved in the greater angiogenic and metastatic capacity of murine melanoma BL6T cells.
Melanoma Res 2000 Dec
PMID:Overexpression of nPKCdelta in BL6 murine melanoma cells enhances TGFbeta1 release into the plasma of metastasized animals. 1119 73

Interferon alpha (IFN-alpha) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. Furthermore, naturally occurring insensitivity to IFN-alpha may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not been identified so far. To explore the molecular basis of IFN-alpha responsiveness, we analysed the expression pattern of about 7000 genes in IFN-alpha sensitive and resistant cell lines and we compared the transcription profiles of cells cultured in the presence or absence of the cytokine using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction upon IFN-alpha treatment by standard 3H-thymidine incorporation and flow-cytometry. The study of 4 sensitive and 2 resistant cell lines allowed the identification of 4 genes (RCC1, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and 2 (SHB and PKC-zeta) preferentially expressed in resistant cells. IFN-alpha stimulation resulted in the expression of a panel of 19 known inducible genes in sensitive but not in resistant cells. Moreover a group of 30 novel IFN-alpha inducible genes was identified. These data may provide a useful basis to develop diagnostic tools to select potential IFN-alpha responders eligible for treatment, while avoiding unnecessary toxicity to non-responders. Furthermore, by extending the knowledge of the polymorphic effects of IFN-alpha on gene expression, they offer novel clues to the study of its pleiotropic toxicity.
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PMID:High density oligonucleotide array analysis of interferon- alpha2a sensitivity and transcriptional response in melanoma cells. 1143 11

As with most cancers, the aetiology of human cutaneous melanoma is likely to be multifactorial and to include the accumulation of irreversible alterations in an unknown number of genes. Elucidating this molecular progression necessitates both the identification of genetic perturbations at each clinically relevant stage, and the assessment of their impact on the normal melanocyte. The observation that the epidermal melanocyte, in contrast to metastatic melanoma cells, requires activation of the protein kinase C (PKC) pathway to facilitate growth in vitro indicates that one or more isoforms (or substrates) of this large and complex family of proteins are among those that undergo alteration during the development of malignant melanoma. Consequently, a number of studies have investigated the expression of various PKC family members in both melanocyte and melanoma cell lines, without a consensus of opinion as to which isoforms are of biological significance in melanoma development and progression. The present study involved a comprehensive evaluation of the PKC profile in normal melanocytes and in 16 metastatic melanoma cell lines. The results show that the major difference in isoform expression between epidermal melanocytes and melanoma cells is the loss of PKCbeta protein expression in 90% of melanoma cell lines. Examination of PKCbeta in benign and malignant melanocytic lesions revealed that this protein is either downregulated or absent in both naevi and metastatic melanomas. We conjecture that, although the loss of PKCbeta expression is a common phenomenon in malignant melanocytes, it may be related more to a normal process of melanocytic differentiation than to malignant transformation.
Melanoma Res 2001 Aug
PMID:Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: a result of transformation or differentiation? 1147 24

Interferon alpha (IFN-alpha) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. In addition, naturally occurring insensitivity to IFN-alpha may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not so far been identified. To explore the molecular basis of IFN-alpha responsiveness, we analyzed the expression pattern of about 7000 genes in IFN-alpha-sensitive and IFN-alpha-resistant cell lines using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction by IFN-alpha by standard 3H-thymidine incorporation and flow cytometry. Total cellular RNA from four sensitive and two resistant cell lines was extracted, reverse-transcribed and hybridized to high-density oligonucleotide arrays. The comparative analysis of gene expression in either set of cell lines allowed the identification of four genes (RCCl, IFI16, hox2 and h19) preferentially transcribed in sensitive cells and two (SHB and PKC-zeta) preferentially expressed in resistant cells. These data may provide a useful basis for the development of diagnostic tools to select potential IFN-alpha responders as eligible for treatment, while avoiding unnecessary toxicity to nonresponders.
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PMID:Interferon-a sensitivity in melanoma cells: detection of potential response marker genes. 1207 43

Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in beta-catenin expression or nuclear translocation was observed. There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade. These observations support a role for Wnt5a in human melanoma progression.
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PMID:Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. 1208 64

Enzymes belonging to the protein kinase C (PKC) family represent one of the major mediators of signal transduction in melanocytes. To identify PKC isoforms that may be associated with the process of malignant transformation and metastasis, we investigated the expression pattern of 11 different PKC isoforms (alpha, beta I, beta II, gamma, delta, epsilon, eta, theta, zeta, lambda, and iota) in melanoma lymph node metastases, in cell lines established from these metastases, in primary cell cultures from normal melanocytes, and in permanent cell lines established from spontaneously transformed melanocytes. PKC alpha, beta I, beta II, delta, epsilon, eta, zeta, lambda and iota were found to be expressed in total lysates from melanoma metastases. In permanent cell lines established from these metastases, the expression levels of PKC beta I, beta II, delta, epsilon, and eta were lower or undetectable when compared with initial expression in tumour lysates. In normal primary melanocyte cultures, the PKC isoforms beta II, delta, epsilon, eta and iota were undetectable. PKC gamma and theta isoforms were undetectable in all melanocytic cell types examined. PKC iota was the only isoform exclusively detected in tumour lysates, in spontaneously transformed melanoma cells and melanoma cell lines, but not in normal melanocytes, and may therefore be associated with the transformed phenotype in human melanoma in vitro and in vivo.
Melanoma Res 2002 Jun
PMID:Protein kinase C isoforms in normal and transformed cells of the melanocytic lineage. 1214 Mar 76

Many studies have attempted to define the state of differentiation of melanoma cells and to correlate it with other critical parameters of malignancy such as the tumorigenic and metastatic nature of the cells. In the present paper we focused on the possible relationships between the novel protein kinase C isoform nPKCdelta, melanin synthesis and proliferative capacity in a primary human melanoma cell line WM115. Cells were transfected to produce overexpression of this isoform and the effects on melanin synthesis, cyclin-E dependent kinase (cdk2) activity and cyclin E expression were studied. It was shown that translocation of nPKCdelta into the nucleus affects melanin synthesis and inhibits cdk2 activity. As a compensatory effect, the level of cyclin E increases. In view of these results we suggest a model for the role of nPKCdelta in melanoma cells that may offer a new therapeutic perspective.
Melanoma Res 2002 Aug
PMID:Higher levels of melanin and inhibition of cdk2 activity in primary human melanoma cells WM115 overexpressing nPKCdelta. 1217 Jan 78

Phospholipase D (PLD) is a highly regulated enzyme involved in lipid-mediated signal transduction processes affecting vesicular trafficking and cytoskeletal reorganization. It is regulated by protein kinase C, adenosine diphosphate (ADP)-ribosylation factors and Rho family proteins, and both protein kinase C and Rho family proteins have been implicated in the metastatic potential of melanoma. We analysed PLD in four human melanoma cell lines and in primary human melanocytes. Melanoma cell lines showed phosphatidylcholine-hydrolysing, phosphatidylinositol 4,5-bisphosphate-dependent PLD activity, which was activated by phorbol ester and a non-hydrolysable guanosine triphosphate (GTP) analogue in a dose-dependent and synergistic manner, whereas primary melanocytes exhibited only low PLD activity compared with the melanoma cell lines. As determined by reverse transcription polymerase chain reaction, both splicing variants of PLD1, PLD1a and PLD1b, and the isoenzyme PLD2, are expressed in melanoma cells and melanocytes. Western blot analysis showed that PLD1 expression was low in primary melanocytes in contrast to melanoma cells, which is in agreement with our finding of low activity. Interestingly, Rho protein mRNA was elevated in all melanoma cell lines. We conclude that in human melanoma cells, the PLD activity that is stimulated by phorbol ester requires ADP-ribosylation factor, protein kinase C and Rho proteins for full activity, and most probably represents the isoenzyme PLD1.
Melanoma Res 2003 Dec
PMID:Expression and regulation of phospholipase D isoenzymes in human melanoma cells and primary melanocytes. 1464 17

In the 1980s, protein kinase C (PKC) was identified as a contributing factor in skin tumorigenesis. As drugs targeting specifically PKC have become available, the intent of this review was to assess the role of PKC, in particular of PKC-alpha in melanoma or other skin cancers. We reviewed and summarized published studies examining the role of PKC-alpha in the development of melanoma or other skin cancers. Most studies to date have been cell-culture based. In models of melanoma, PKC-alpha activation is typically associated with increased tumour cell proliferation, invasiveness and decreased differentiation, suggesting that PKC-alpha inhibitors, such as aprinocarsen, an antisense oligonucleotide directed against PKC-alpha, may be appropriate in the treatment of skin malignancies. Because of the recent developments on selective or specific PKC-alpha inhibitors, including aprinocarsen, there is a growing need to conduct further translational research, especially in melanoma patients, to identify the patient population that might benefit most from PKC-alpha targeted therapy.
Melanoma Res 2004 Apr
PMID:The role of protein kinase C-alpha (PKC-alpha) in melanoma. 1505 36


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