Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.13.3 (histidine kinase)
 2,405 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nm23 genes were discovered on the basis of their reduced expression by highly metastatic cell lines. This trend was confirmed in cohorts of several types of human carcinomas and melanomas. Several transfection studies have demonstrated the suppressive effect of nm23 overexpression on the metastatic aggressiveness of melanoma and breast carcinoma cells in vivo. These transfection experiments have also demonstrated an effect of nm23 overexpression on cellular functions involved in the metastatic phenotype, such as cell motility, and point to a regulatory role for Nm23 proteins in cellular signalling pathways. Nm23 homologues from various species are also involved in normal tissue development and differentiation. Transfection of nm23-H1 into breast cancer cells provided a functional demonstration of the involvement of this gene in the differentiation of mammary epithelial cells. However, the molecular mechanism of these biological effects remains unknown. Several biochemical activities have been reported for Nm23, including NDP kinase activity, serine autophosphorylation and protein-histidine kinase activity. To define the possible significance of these biochemical activities, we carried out site-directed mutagenesis of the relevant codons of nm23-H1 cDNA and studied the effects upon transfection into MDA-MB-435 human breast carcinoma cells. We have also used Nm23 expression as a molecular marker to identify novel compounds that are active against the most aggressive tumour cells. This approach revealed that none of the standard agents currently in clinical use is preferentially active against the most aggressive tumour cells, and allowed us to identify new compounds that are preferentially inhibitory towards low-Nm23-expressing breast carcinoma and melanoma cell lines. This analysis also revealed a significant correlation between Nm23 levels and sensitivity of the tumour cells to alkylating agents. A functional implication of Nm23 proteins in this phenomenon was demonstrated after transfection of nm23 cDNAs into melanoma and breast and ovarian carcinoma cells.
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PMID:Nm23 and tumour metastasis: basic and translational advances. 951 29

Dicarboximides and phenylpyrroles are commonly used fungicides against plant pathogenic ascomycetes. Although their effect on fungal osmosensing systems has been shown in many studies, their modes-of-action still remain unclear. Laboratory- or field-mutants of fungi resistant to either or both fungicide categories generally harbour point mutations in the sensor histidine kinase of the osmotic signal transduction cascade.In the present study we compared the mechanisms of resistance to the dicarboximide iprodione and to pyrrolnitrin, a structural analogue of phenylpyrrole fungicides, in Botrytis cinerea. Pyrrolnitrin-induced mutants and iprodione-induced mutants of B. cinerea were produced in vitro. For the pyrrolnitrin-induced mutants, a high level of resistance to pyrrolnitrin was associated with a high level of resistance to iprodione. For the iprodione-induced mutants, the high level of resistance to iprodione generated variable levels of resistance to pyrrolnitrin and phenylpyrroles. All selected mutants showed hypersensitivity to high osmolarity and regardless of their resistance levels to phenylpyrroles, they showed strongly reduced fitness parameters (sporulation, mycelial growth, aggressiveness on plants) compared to the parental phenotypes. Most of the mutants presented modifications in the osmosensing class III histidine kinase affecting the HAMP domains. Site directed mutagenesis of the bos1 gene was applied to validate eight of the identified mutations. Structure modelling of the HAMP domains revealed that the replacements of hydrophobic residues within the HAMP domains generally affected their helical structure, probably abolishing signal transduction. Comparing mutant phenotypes to the HAMP structures, our study suggests that mutations perturbing helical structures of HAMP2-4 abolish signal-transduction leading to loss-of-function phenotype. The mutation of residues E529, M427, and T581, without consequences on HAMP structure, highlighted their involvement in signal transduction. E529 and M427 seem to be principally involved in osmotic signal transduction.
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PMID:Functional and structural comparison of pyrrolnitrin- and iprodione-induced modifications in the class III histidine-kinase Bos1 of Botrytis cinerea. 2291 6

Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. NPC frequently metastasizes to the bone in advanced patients resulting in high mortality. The molecular mechanisms for NPC development and cancer-induced bone lesions are unclear. In this study, we firstly determined chemokine receptor CCR2 and CXCR6 expressions in clinical specimens and CNE2, SUNE1, CNE1, and HK1 cell lines. Then, we measured chemokine CCL2 and CXCL16 production in these NPC cell lines by ELISA. Expression levels of these chemokines and their receptors were observed to positively correlate with tumor aggressiveness. Furthermore, U0126 (MEK inhibitor) was used to treat these NPC cell lines. CCL2 and CXCL16 expression levels and cell proliferation were significantly inhibited by U0126 in a dose- and time-dependent manner. Finally, we collected conditioned medium (CM) from NPC cell cultures in the presence of U0126 treatment. When mouse bone marrow non-adherent cells were treated with the CM, the numbers of multinucleated osteoclast formation were dramatically diminished. These results indicate that MEK inhibitor diminishes NPC cell proliferation and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. This study provides novel therapeutic targets such as CCL2/CCR2 and CXCL16/CXCR6 for advanced NPC patients.
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PMID:MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. 2605 73