Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have found that three phenotypically dissimilar mouse B16 melanoma subclones are competent recipients for DNA-mediated gene transfer. Two of these approach and a third, amelanotic clone B78H1, surpasses mouse LTK cells in frequencies of transferent colony formation after treatment with either of two codominantly selectable plasmid vectors, pSV2gpt or pGCcos3neo. Melanoma transferents incorporate both selectable plasmid-homologous sequences and substantial amounts of unselected donor DNA into their cellular DNAs. In addition they retain the distinctive states of differentiation characteristic of the untreated clones. Frequencies of pGCcos3neo-mediated transfer of neo gene-encoded antibiotic resistance into B78H1 can reach 10(-2) in response to treatment with as little as 15 ng plasmid/ml coprecipitate/dish. B78H1 cells readily give rise to "secondary" transferents for the neo gene after treatment with DNA from a "primary" B78H1 neo transferent. This gene transfer system has potential applications for study of regulation of melanoma and neural crest differentiation and malignancy.
...
PMID:Efficient DNA-mediated transfer of selectable genes and unselected sequences into differentiated and undifferentiated mouse melanoma clones. 632 93

Epithelial cell kinase (ECK) is a receptor protein tyrosine kinase, the role of which in melanoma biology is unclear. Here we studied the role of ECK during melanoma progression. ECK mRNA was overexpressed in virtually all melanoma lines tested, and levels were significantly higher in cell lines from distant metastases than primary melanomas; melanocytes were negative. Gene amplification was not detected in melanomas. Levels of ECK protein corresponded well with mRNA levels. B61 or LERK-1, recently identified as an ECK ligand, stimulated the growth of ECK-expressing melanoma cell lines, its first identified biological activity. Melanoma chemotaxis and chemoinvasion were not affected by B61. Growth of normal melanocytes was not affected. mRNA for B61 was detected in both melanoma cell lines and normal melanocytes. B61 was also identified by Western blotting and ECK binding activity with the use of a BIAcore binding assay in melanoma cell-conditioned media. These results suggest that B61 is an autocrine growth factor for melanomas but not normal melanocytes.
...
PMID:Protein B61 as a new growth factor: expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression. 778 Sep 63

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

To investigate the role of c-KIT receptor in melanocytic tumour development and progression, we analysed the expression and localization of c-KIT by immunohistochemistry and Western blotting. In contrast to the positive staining shown by melanocytes and naevus cells in the epidermis of common naevi (n=20), all dysplastic naevi (n=13) were negative, as were dermal melanocytic cells of blue naevi (n = 4) and common naevi (n = 26). Three out of four superficial spreading melanomas lost c-KIT expression both in the epidermal and dermal parts, while nodular melanomas showed no expression of c-KIT except in partially positive cells, and six out of seven metastatic melanomas were negative. In acral lentiginous melanomas (n = 8), in contrast to other types of melanoma, all cases with melanoma cells growing basally in the epidermis showed strong c-KIT positivity, but melanoma cells growing at the upper layers of the epidermis and vertically into the dermis lost c-KIT expression. Using the Western blot method on cultured pigment cells, human epidermal melanocytes, junctional naevus cells and one out of three metastatic melanoma cell lines showed 125 and 145 kDa bands corresponding to c-KIT, whereas dermal naevus cells did not. These results suggest that dysplastic naevi are distinct from ordinary naevi in terms of c-KIT expression and that basally growing cells in acral lentigenous melanomas could be at an initial stage of tumour progression, before c-KIT loss occurs.
Melanoma Res 1996 Feb
PMID:c-KIT receptor expression in cutaneous malignant melanoma and benign melanotic naevi. 864 66

Fibroblast growth factor 2 (FGF2) has been implicated in the pathogenesis of malignant melanoma (MM), but the role of other FGFs and their receptors (FGFRs) is not elucidated. To determine whether FGF1 and FGFR1 may be involved in MM growth in vivo, we have studied the expression of the FGF1 and FGFR1 genes in 77 fresh MM biopsy samples, using RT-PCR analysis. Samples of benign nevi, normal skin and carcinoma cell lines were included as controls. Using RT-PCR analysis, expression of FGF1 and FGFR1 was observed in 69/77 and 68/77 cases, respectively. Immunohistochemical detection of the FGFR1 protein was positive in reactive stromal cells and at a much lower level in neoplastic cells. In situ hybridization experiments demonstrated FGFR1 mRNA mainly located in the stromal component. Southern blot analysis of genomic DNA prepared from MM tumors did not show any structural alteration of the FGFR1 gene. There was no correlation between FGF1/FGFR1 expression and the usual clinicopathological parameters of MM. We conclude that FGF1 and FGFR1 are frequently co-expressed in MM, a situation that may contribute to aberrant autocrine and paracrine pathways. Due to the absence of correlation with clinico-pathological parameters, this expression cannot be used as a marker of prognosis in the management of MM patients.
Melanoma Res 1996 Jun
PMID:Expression of FGF1 and FGFR1 in human melanoma tissues. 881 25

Melanoma formation in Xiphophorus is initiated by overexpression of an oncogenic version of the EGFR-related receptor tyrosine kinase Xmrk (Xiphophorus melanoma receptor kinase). High steady-state levels of Xmrk oncogene mRNA are found in malignant melanoma; however, this overabundance of transcripts appears to be not sufficient for manifestation of the full oncogenic potential of Xmrk. In addition, several amino acid exchanges cause the oncogenic receptor to be highly active, resulting in a strong tyrosine phosphorylation even without growth factor stimulation. Besides the receptor itself a Xmrk-specific signal transduction seems to be a critical part of the transformation machinery. Expression experiments in transgenic fish indicate that the Xmrk-mediated intracellular signalling is contributing to the cell-type specificity in development of hereditary melanoma in Xiphophorus.
...
PMID:Signal transduction by the oncogenic receptor tyrosine kinase Xmrk in melanoma formation of Xiphophorus. 917 Jan 60

Melanoma formation in Xiphoporus is initiated by overexpression of the EGFR-related receptor tyrosine kinase Xmrk (Xiphoporus melanoma receptor kinase). This receptor is activated in fish melanoma as well as in a melanoma-derived cell line (PSM) resulting in constitutive Xmrk-mediated mitogenic signaling. In order to define the underlying signaling pathway(s), triggered by the activated Xmrk receptor, we attempted to identify its physiological substrates. Examination of the Xmrk carboxyterminus for putative tyrosine autophosphorylation sites revealed the presence of potential binding motifs for GRB2 as well as for Shc. Binding of these adaptor proteins to the Xmrk receptor was detected in vitro and in cells expressing the mrk kinase. The GRB2 and Shc interactions with the receptor could be disrupted individually by phosphotyrosine peptides containing putative Xmrk autophosphorylation sites, indicating direct binding of both proteins. Recruitment of GRB2 by the constitutively activated Xmrk receptor led to strong MAP kinase activation in Xiphoporus melanoma cells. We also identified a high-affinity binding site for src-kinases (pYEDL) in the Xmrk carboxyterminus. Competition experiments with phosphopeptides comprising this site confirmed that it is used for high-affinity binding of Xiphoporus fyn (Xfyn) to Xmrk in melanoma cells. Thus, Xmrk can initiate different signaling pathways by using multiple substrate-binding sites to trigger proliferation of pigment cells.
...
PMID:Multiple binding sites in the growth factor receptor Xmrk mediate binding to p59fyn, GRB2 and Shc. 1009 8

Protein tyrosyl phosphorylation is an essential component in intracellular signalling, with diverse and crucial functions including mediation of cell proliferation, survival, death, differentiation, migration and attachment. It is regulated by the balance between the activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases. A number of PTKs are encoded by proto-oncogenes or viral oncogenes, and are thus strongly implicated in cancer. While a role for PTKs in human melanoma is less firmly established, human melanomas or melanoma cells have been reported to contain more tyrosine phosphate than normal melanocytes, and some receptor PTKs (EPH-A2/ ECK and EPH-B3) are overexpressed in over 90% of melanoma cell lines. Other specific PTKs are also frequently overexpressed, including KDR and fibroblast growth factor receptor-4 (FGF-R4), while, interestingly, yet others, such as KIT and FES, are consistently downregulated in melanoma cell lines. All of these differentially expressed PTKs are candidates for gene products important in melanoma development. In addition, PTKs expressed in significant amounts in both benign and malignant melanocytes, such as insulin-like growth factor-1 receptor (IGF1-R), FGF-R1, HER2/NEU and FAK, are likely to play a role in melanoma genesis and progression.
Melanoma Res 2000 Oct
PMID:Protein tyrosine kinases in malignant melanoma. 1109

The regulation of apoptosis is believed to be dependent on the balance of the activities of different intracellular signalling systems. Activation of the SAPK/JNK pathway is implied in pro-apoptotic signalling, while activation of the MEK1/ERK pathway may have a viability-promoting effect. We show here that treatment with the MEK1 inhibitor PD98059 sensitizes the human melanoma cell line C8161 to cisplatin-induced apoptosis. In these cells, cisplatin at 40 microM did not elicit significant cell death, whereas massive cell death was seen when cells were pretreated for 20 h with 40 microM PD98059 before the addition of cisplatin. Concomitant addition of PD98059 and cisplatin did not have any sensitizing effect, and PD98059 on its own did not induce apoptosis. However, in three other human melanoma cell lines PD98059 did not potentiate cisplatin-induced apoptosis. Instead, in one of these cell lines (AA), PD98059 protected against cisplatin-induced cytotoxicity. We conclude that blocking of the MEK1/ERK pathway may, in some instances, potentiate the cytotoxic effect of cisplatin on human melanoma cell lines, whereas in other instances it may have a protective effect. Thus it cannot be regarded as a general approach to sensitizing melanoma cells to drug-induced apoptosis.
Melanoma Res 2001 Feb
PMID:The MEK1 inhibitor PD98059 sensitizes C8161 melanoma cells to cisplatin-induced apoptosis. 1125 11

Melanoma cells can undergo self-destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti-apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c-KIT/SCF. The latter include Bcl-2, Bcl-X(L), Mcl-1, NF-(K)B, survivin, livin, and ML-IAP. Alternatively, some molecules such as TRAF-2, c-Myc, endothelins, and integrins may have either pro- or anti-apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl-1 and Bcl-X(L), which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF-(K)B, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research.
...
PMID:Apoptosis and melanoma: molecular mechanisms. 1451 53


1 2 3 4 5 6 7 8 9 10 Next >>

---