Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adequate production of blood cells is sustained by pluripotent hemopoietic progenitors whose behavior is influenced by a permissive hemopoietic microenvironment. Hemopoietic progenitors have in common the expression of CD34 surface molecules, but are heterogeneous with respect to other properties. It is commonly accepted that primitive progenitors, considered to be candidates for marrow repopulating cells, are HLA-DR-, without expressing lineage-specific determinants. They are usually quiescent with respect to their cell cycle status. In addition to CD34, they may display adhesion molecules on their surface and express receptors for ligands such as c-kit, FLT2/FLK3 and various other cytokines. Some of these are expressed constitutively, while others emerge as the cells progress through their regular maturation program. This process appears to include a gradual reduction of their proliferative capabilities as demonstrated by a progressive loss of the length of their telomeric structures.
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PMID:Assessment and characterization of hemopoietic stem cells. 874 83

Comparative mapping data suggested that the dominant white coat color in pigs may be due to a mutation in KIT which encodes the mast/stem cell growth factor receptor. We report here that dominant white pigs lack melanocytes in the skin, as would be anticipated for a KIT mutation. We found a complete association between the dominant white mutation and a duplication of the KIT gene, or part of it, in samples of unrelated pigs representing six different breeds. The duplication was revealed by single strand conformation polymorphism (SSCP) analysis and subsequent sequence analysis showing that white pigs transmitted two nonallelic KIT sequences. Quantitative Southern blot and quantitative PCR analysis, as well as fluorescence in situ hybridization (FISH) analysis, confirmed the presence of a gene duplication in white pigs. FISH analyses showed that KIT and the very closely linked gene encoding the platelet-derived growth factor receptor (PDGFRA) are both located on the short arm of Chromosome (Chr) 8 at band 8p12. The result revealed an extremely low rate of recombination in the centromeric region of this chromosome, since the closely linked (0.5 cM) serum albumin (ALB) locus has previously been in situ mapped to the long arm (8q12). Pig Chr 8 shares extensive conserved synteny with human Chr 4, but the gene order is rearranged.
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PMID:Pigs with the dominant white coat color phenotype carry a duplication of the KIT gene encoding the mast/stem cell growth factor receptor. 887 90

An 8-year-old boy who was diagnosed to have piebaldism had moderate growth and mental retardation. Chromosome analysis from peripheral blood showed pericentric inversion 4(p16q12). The inversion was further confirmed by fluorescence in situ hybridization using whole chromosome painting and centromeric probes. Chromosomal analysis of parents revealed de novo inheritance of this inversion. This is the first report of pericentric inversion associated with piebald trait.
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PMID:De novo pericentric inversion of chromosome 4, inv(4)(p16q12) in a boy with piebaldism and mental retardation. 1240 11

Telomerase activity was examined by the telomeric repeat amplification protocol (TRAP) assay in 38 neuroendocrine (NE) lung tumours. A significantly (p = 0.001) different frequency of telomerase positivity was observed among different histological tumour types. Specifically, a positive TRAP signal was observed in 14 of 15 (93%) small cell lung cancers (SCLCs), 7 of 8 (87%) large-cell NE carcinomas (LCNECs), and only 1 of 15 (7%) typical carcinoid tumours. When telomerase activity was correlated with the gene product-based immunophenotypic profile of individual tumours, it was found that the absence of telomerase activity was associated with a lack of bcl-2, p53, and c-kit expression, and characterized by a low proliferation index consistent with the absence of cdk-4 expression and the presence of the cdk inhibitor Rb. Such a phenotype was appreciable in most of the carcinoid tumours. Conversely, telomerase-positive tumours generally showed an immunophenotype consistent with gene product alterations (including high expression of bcl-2, p53, and c-kit, and loss of Rb) and were characterized by a high proliferation index. These telomerase data support the previously reported evidence for two genetically unrelated groups of NE lung tumours (SCLC, and to some extent LCNEC, versus carcinoid tumours) that have distinct phenotypic profiles.
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PMID:Differential expression of telomerase activity in neuroendocrine lung tumours: correlation with gene product immunophenotyping. 1295 25

Herein we report on the synthesis and DNA binding properties of a new class of water soluble oxazole-based peptide macrocycles that bind selectively to quadruplex DNA, with no detectable binding to duplex DNA. We have recently identified one quadruplex in the proto-oncogene c-kit that is suspected to act as a regulatory element for the expression of the c-kit gene. Here we provide the first example of a ligand binding to and stabilizing the c-kit quadruplex. Moreover, we show that these macrocycles show a preference for the c-kit quadruplex as compared to the human telomeric quadruplex.
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PMID:Oxazole-based peptide macrocycles: a new class of G-quadruplex binding ligands. 1704 74

Guanine-rich DNA sequences can form G-quadruplexes stabilized by stacked G-G-G-G tetrads in monovalent cation-containing solution. The length and number of individual G-tracts and the length and sequence context of linker residues define the diverse topologies adopted by G-quadruplexes. The review highlights recent solution NMR-based G-quadruplex structures formed by the four-repeat human telomere in K(+) solution and the guanine-rich strands of c-myc, c-kit and variant bcl-2 oncogenic promoters, as well as a bimolecular G-quadruplex that targets HIV-1 integrase. Such structure determinations have helped to identify unanticipated scaffolds such as interlocked G-quadruplexes, as well as novel topologies represented by double-chain-reversal and V-shaped loops, triads, mixed tetrads, adenine-mediated pentads and hexads and snap-back G-tetrad alignments. The review also highlights the recent identification of guanine-rich sequences positioned adjacent to translation start sites in 5'-untranslated regions (5'-UTRs) of RNA oncogenic sequences. The activity of the enzyme telomerase, which maintains telomere length, can be negatively regulated through G-quadruplex formation at telomeric ends. The review evaluates progress related to ongoing efforts to identify small molecule drugs that bind and stabilize distinct G-quadruplex scaffolds associated with telomeric and oncogenic sequences, and outlines progress towards identifying recognition principles based on several X-ray-based structures of ligand-G-quadruplex complexes.
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PMID:Human telomere, oncogenic promoter and 5'-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics. 1791 50

G-quadruplexes are believed to be potential targets for therapeutic intervention and this has resulted in designing of various quadruplex interacting ligands. Moreover, reports about existence of quadruplex forming sequences across the genome have propelled greater interest in understanding their interaction with small molecules. An intramolecular quadruplex sequence can adopt different conformations, owing to different orientation of loops in the structure. The differences in the loop orientation can affect their molecular recognition. Herein, we have studied the interaction of 5,10,15,20-tetrakis(1-methyl-4-pyridyl)-21H, 23H-porphine (TMPyP4), a well-known G quadruplex binding ligand with three DNA quadruplexes differing in loop orientations. Results obtained from UV, ITC, and SPR studies have coherently revealed that the TMPyP4 molecule shows preferential binding to parallel G-quadruplex ( c-myc and c-kit) over its antiparallel counterpart (human telomeric). The binding affinity for parallel quadruplex was (10(7)) 1 order of magnitude higher than that for antiparallel DNA quadruplex (10 ). The study shows two binding modes, stronger binding (10(7)) of TMPyP4 involving end stacking and a weaker external binding (10 ), while TMPyP4 shows only one binding mode with duplex with a binding affinity of the order of 10(6). Overall, the study emphasizes that differences in the loop orientation give rise to different conformations of quadruplex, which in turn govern its binding to small molecules, and thereby play a pivotal role in molecular recognition.
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PMID:Effect of loop orientation on quadruplex-TMPyP4 interaction. 1855 64

We have explored a series of trisubstituted acridine-peptide conjugates for their ability to recognize and discriminate between DNA quadruplexes derived from the human telomere, and the c-kit and N-ras proto-oncogenes. Quadruplex affinity was measured as the peptide sequences were varied, together with their substitution position on the acridine, and the identity of the C-terminus (acid or amide). Surface plasmon resonance measurements revealed that all compounds bound to the human telomeric quadruplex with sub-micromolar affinity. Docking calculations from molecular modelling studies were used to model the effects of substituent orientation and peptide sequence. Modelling and experiment were in agreement that placement of the peptide over the face of the acridine is detrimental to binding affinity. The highest degrees of selectivity were observed towards the N-ras quadruplex by compounds capable of forming simultaneous contacts with their acridine and peptide moieties. The ligands that bound best displayed quadruplex affinities in the 1-5 nM range and at least 10-fold discrimination between the quadruplexes studied.
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PMID:Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates. 1908 49

We report CD, ESI-MS and molecular modelling studies of ligand binding interactions with DNA quadruplex structures derived from the human telomeric repeat sequence (h-Tel) and the proto-oncogenic c-kit promoter sequence. These sequences form anti-parallel (both 2 + 2 and 3 + 1) and parallel conformations, respectively, and demonstrate distinctively different degrees of structural plasticity in binding ligands. With h-Tel, we show that an extended heteroaromatic 1,4-triazole (TRZ), designed to exploit pi-stacking interactions and groove-specific contacts, shows some selectivity for parallel folds, however, the polycyclic fluorinated acridinium cation (RHPS4), which is a similarly potent telomerase inhibitor, shows selectivity for anti-parallel conformations implicating favourable interactions with lateral and diagonal loops. In contrast, the unique c-kit parallel-stranded quadruplex shows none of the structural plasticity of h-Tel with either ligand. We show by quantitative ESI-MS analysis that both sequences are able to bind a ligand on either end of the quadruplex. In the case of h-Tel the two sites have similar affinities, however, in the case of the c-kit quadruplex the affinities of the two sites are different and ligand-dependent. We demonstrate that two different small molecule architectures result in significant differences in selectivity for parallel and anti-parallel quadruplex structures that may guide quadruplex targeted drug-design.
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PMID:Selectivity of small molecule ligands for parallel and anti-parallel DNA G-quadruplex structures. 1979 57

AIE molecule silole 1 could be used to detect G-quadruplex formation using an exonuclease I hydrolysis assay. This visual observation of G-quadruplexes has been successfully used in investigating multiple G-quadruplexes, including the one-stranded telomeric, c-myc, c-kit, VEGF G-quadruplexes, and a d(G(4)T(4)G(4)) inter-molecular G-quadruplex. The detection of G-quadruplex can be also applied to G-quadruplex isomers induced by small molecules.
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PMID:Visual observation of G-quadruplex DNA with the label-free fluorescent probe silole with aggregation-induced emission. 1982 30


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