Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The WAF1 gene, located on chromosome 6p, encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes that are necessary for cells to exit Gr. Transcriptional activation of WAF1 can be accomplished by increasing levels of p53 protein induced by various cellular stresses, including DNA damage. Metastatic melanomas are paradoxical in that most overexpress wild-type p53 protein, yet cell growth is not inhibited. Thus, it is possible that lack of growth suppression in melanomas is due, in part, to mutations in the WAF1 gene. Therefore, we examined the entire coding region of the WAF1 gene in 24 metastatic melanoma cell lines and three normal melanocyte lines by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. We similarly examined the DNA from lymphoblastoid cell lines, derived from nine individuals belonging to seven melanoma-prone families, in which haplotypes of markers on 6p cosegregate with melanoma for germline mutations in the WAF1 gene. Results indicate that (i) mutation of the WAF1 gene is an infrequent event in individuals with sporadic melanoma or predisposed to familial melanoma and (ii) the uncontrolled growth of melanoma cells is not due to mutation of the WAF1 gene. However, expression studies found a wide variation in the level of p21 protein in melanoma cells, suggesting that aberrant regulation of p21 may play a role in melanoma development. Moreover, there was no predictable relationship between p21 expression and p53 expression, indicating that other, p53-independent, pathways may be important for the regulation of p21 in melanoma cells.
Melanoma Res 1995 Aug
PMID:Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. 749 59

Aberrant function of protein kinases has been implicated in the development of melanoma. In an effort to define the molecular events involved in initiation and progression of this malignancy, we used RT-PCR to identify protein kinases in both normal and transformed melanocytes. Collectively, we identified seven clones corresponding to previously characterized protein kinases (JAK-1, TYK02, AXL/UFO, IGF1-R, KDR and FER) as well as the recently identified MLK-3/PTK1 protein kinase. Northern analysis was used to determine the expression pattern of each protein kinase in both normal melanocytes and a variety of melanoma cell lines. Relatively abundant levels of UFO/AXL and KDR mRNAs were observed in a subset of the melanoma cell lines whereas most of the remaining protein kinases were expressed at similar levels in both normal and transformed melanocytes.
Melanoma Res 1994 Oct
PMID:Protein kinases in normal and transformed melanocytes. 785 16

The induction of differentiation, as evidenced by benign growth characteristics, dendritic morphology, pigmentation capability, and a mature antigenic phenotype, is an attractive theoretical basis for therapy in human melanoma. Melanoma differentiation can be experimentally induced by modulating intracellular pathways involving protein kinase C, tyrosine kinases, and protein kinase A, or by modulating nuclear transcription with retinoids, DNA-damaging agents, and chemotherapeutic drugs. Other experimental differentiating agents include the amino acid tyrosine, histamine receptor antagonists, polyamine antagonists, dimethylsulphoxide, caffeic acid ester, and butyrate. The mechanisms involved in the actions of many of these agents are beginning to be understood and the pathways are often intersecting; cross-talk in the form of negative and positive feedback loops is extensive. Uncoupling of pathways is also seen, with some agents leading to simultaneous increases in both differentiated and transformed characteristics. While clinical benefits of this approach have so far been sparse, greater understanding of the cellular pathways of differentiation may open new therapeutic options in melanoma.
Melanoma Res 1994 Aug
PMID:Cellular pathways leading to melanoma differentiation: therapeutic implications. 795 Mar 57

We have recently identified a gene encoding a calnexin-like protein (p90) by the immunoscreening of a human melanoma cDNA library, using a rabbit anti-human melanosomal antibody. This p90 protein was highly expressed by human melanocytes and associated with melanosomal membrane and endoplasmic reticulum. In this study we report the computer analysis of the predicted amino acid sequence of this calnexin-like melanosomal protein. We found that p90 is a membrane-bound protein whose large N-terminal domain is located within the melanosomal compartment; its shorter C-terminal is exposed to the cytosol and separated by a short transmembrane region. This p90 protein was found to have consensus sequences of a Ca(2+)-binding loop and a protein kinase C phosphorylation site at the N-terminal domain. The C-terminal domain, on the other hand, contained sequences of a casein kinase II phosphorylation site and two protein kinase A phosphorylation sites. Such functional motifs could provide signal transduction across the melanosomal membrane, the reception of melanogenic protein via carriers at the melanosomal membrane and the translocation of melanosomes in the melanocyte.
Melanoma Res 1993 Aug
PMID:cDNA-based functional domains of a calnexin-like melanosomal protein, p90. 821 59

The retinoblastoma protein (pRb) pathway is critical in regulating the G1 phase of the cell cycle and it is frequently disrupted in human cancers. Components of the pRb pathway which are often altered in tumour progression include the INK4 cyclin-dependent kinase (CDK) inhibitors p16INK4a/ CDKN2A and p15INK4b/CDKN2B, CDK4, D-type cyclins and pRb. Several of these components were studied in a series of cultured melanoma cell lines in order to determine the frequency and spectrum of genetic alterations and to define targets for potential gene transfer studies. Also studied were the p16INK4a alternate transcript (p14ARF) and the p21(waf1) CDK inhibitor. The majority of the melanoma cell lines tested (13 out of 17; 76%) carried mutated (two), deleted (nine) or silenced (two) p16(INK4a). CDK4 was mutated or overexpressed in two melanoma cell lines with homozygously deleted CDKN2A and CDKN2B genes. This suggests that the selective growth advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct and may involve the mediation of other CDK inhibitors or CDKs.
Melanoma Res 1999 Feb
PMID:Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured melanoma cells. 1033 30

We postulate that genes involved in the control of cell proliferation are important determinants of melanoma growth and/or transformation. Using Western blot analysis, we compared the expression of nine key cell cycle regulators in metastatic melanomas with that in benign acquired naevi. Among the cyclin-dependent kinases (CDKs) examined, CDK2 was consistently and significantly overexpressed (three- to eight-fold) in metastatic melanomas compared with naevi. CDK1 and CDK4 exhibited no significant difference in expression between benign naevi and metastatic melanomas. CDK6 expression was variable, with four out of 10 metastatic melanomas showing higher expression than naevi. All the cyclins examined, especially cyclins A and D, were expressed more in metastatic melanomas than in naevi. Cyclin E was not detected in benign naevi, but was easily detectable in most of the metastatic melanomas. In addition, there was significantly greater expression of CDC25A, a tyrosine phosphatase that activates CDK kinases, in the metastatic melanomas. Over-expression of CDK2, CDK6, CDC25A and cyclin A was confirmed in melanoma cell lines. These cell cycle regulators may play an important role in melanoma growth and/or transformation.
Melanoma Res 1999 Apr
PMID:Expression of cell cycle regulators in human cutaneous malignant melanoma. 1038 Sep 37

The ability of human recombinant interferon-alpha2a (IFNalpha2a) to induce the expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1 consequent to signal transducers and activators of transcription (STAT) protein activation was investigated in six human melanoma cell lines with different susceptibilities to the antiproliferative effect of the cytokine. All the cell lines expressed IFNalpha and IFNalpha/beta receptors. Exposure for 24 h to IFNalpha2a markedly enhanced the nuclear expression of STAT1 and STAT2 proteins in all the cell lines. However, no induction of p21waf1 or p27kip1 was consistently observed. Overall, results from the study suggest that the induction of such cyclin-dependent kinase inhibitors is not a major mechanism for the antiproliferative effect of IFNalpha2a, at least in human melanoma cell lines.
Melanoma Res 1999 Oct
PMID:Lack of p21waf1 and p27kip1 protein induction by interferon-alpha2a in human melanoma cell lines. 1059 12

The increasing incidence of melanoma and the lack of effective treatment, with the exception of tumour excision before the onset of the metastatic phase, make it important to identify genes that may function as new molecular markers for diagnosis and/or prognosis or as new targets for therapy. Recently, a new technique using high density oligonucleotide arrays has been developed to simultaneously screen for the expression of thousands of genes. We used this technique to compare the mRNA expression patterns of two human melanoma cell lines with different metastatic behaviour. Eight differentially expressed genes, namely apolipoprotein CII, tyrosinase-related protein 1, transforming growth factor-beta superfamily, subtilisin-like protein, elongation factor 1 alpha2, alpha2-macroglobulin, human cell division cycle 10 and serine/threonine protein kinase (DYRK1A), were selected to validate the array results by Northern blotting and reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, a reliable correlation between differential expression of these genes in the melanoma cell lines and in fresh lesions of melanocytic tumour progression was demonstrated by RT-PCR analysis. Altogether, our data indicate that high density oligonucleotide arrays are a valuable and reliable tool to screen for differentially expressed genes, and that our study may be considered a basic step in the characterization of genes that are involved in the (malignant) progression of melanoma.
Melanoma Res 2002 Feb
PMID:Differentially expressed genes identified in human melanoma cell lines with different metastatic behaviour using high density oligonucleotide arrays. 1182 59

beta-Catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor- and lymphoid enhancer factor-regulated gene transcription. The level of beta-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation sites of the beta-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of beta-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor beta-catenin mutations; in vivo, however, cellular accumulation of beta-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. beta-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of beta-catenin in these cases. Cellular expression of beta-catenin was evaluated by immunohistochemistry and by reverse polymerase chain reaction (RT-PCR) in 80 and 70 cases, respectively. Immunohistochemistry revealed a significant loss of membranous beta-catenin staining between the primary and metastatic melanomas as well as between radial and vertical growth phase. RT-PCR showed a significant inverse correlation between the amount of RNA and the proportion of cells with membranous expression of beta-catenin (P =.0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of beta-catenin. In conclusion, nuclear expression of beta-catenin is seen in cutaneous melanoma but, in contrast to the case of many other cancers, does not correlate with tumor stage or mutation status. A combination of immunohistochemistry and RT-PCR showed that down-regulation of membranous beta-catenin was associated with an increased amount of beta-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of beta-catenin in cutaneous melanoma.
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PMID:Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations. 1195 Sep 21

Melanoma is one of the fastest rising malignancies in the United States. When detected early, primary melanomas are curable through surgery. However, despite significant improvements in diagnosis and surgical, local and systemic therapy, mortality rate in metastatic melanoma remains high. Furthermore, genetic alterations associated with the development and stepwise progression of melanoma, are still unclear. Previous reports show that the catalytic kinase subunit of the cAMP-dependent protein kinase is secreted by tumor cells and can be detected in the serum of cancer patients. We examine in this report the clinical significance of this secreted C subunit kinase termed extracellular protein kinase (ECPKA) in melanoma patients. Our results showed the presence of ECPKA activity in the serum of melanoma patients and correlate with the appearance and size of the tumor. Most importantly, surgical removal of melanoma causes a precipitous decrease in ECPKA activity in the sera of patients, suggesting that ECPKA may be a novel predictive marker in melanoma.
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PMID:Extracellular cAMP-dependent protein kinase (ECPKA) in melanoma. 1514 77


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