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

Inhibiting tyrosine kinases has recently emerged as a therapeutic modality in several forms of neoplasia. The tyrosine kinase inhibitor STI571 (IMATINIB MESYLATE; GLEEVEC; GLIVEC) is a case in point as it has shown promise in the treatment of malignancies expressing the BCR/ABL fusion protein. In addition to BCR/ABL, STI571 inhibits the tyrosine kinase moieties of several cell surface receptors including the platelet-derived growth factor (PDGF) receptors and c-Kit. Previous work demonstrated that c-Kit activation supports migration, invasion and, survival of certain colorectal carcinoma cells including DLD-1. Here we describe that blocking c-Kit with STI571 inhibits these malignant traits not only in DLD-1 cells but also in two early passage colorectal carcinoma cell strains. Specifically, STI571 inhibited anchorage-independent colony formation and cell scattering in semi-solid medium. Furthermore, it enhanced apoptosis susceptibility and abrogated invasion of DLD-1 cells through Matrigel. In addition, STI571 treatment affected the balance of the Bcl-2 family of apoptosis regulators on favor of a pro-apoptotic phenotype. Specifically, STI571 treatment of DLD-1 cells was associated with lower levels of Bcl-2 expression accompanied by de novo expression of Bcl-xS. Finally, STI571 acted as a chemosensitizing agent in DLD-1 cells when used in combination with 5-fluorouracil.
 ...
PMID:Inhibition of cell survival and invasive potential of colorectal carcinoma cells by the tyrosine kinase inhibitor STI571. 1500 35

Mesenchymal proliferations presenting as mucosal polyps are relatively uncommon and are represented by gastrointestinal stromal tumors, smooth muscle and neural tumors, and inflammatory fibroid polyps. In this report, we describe the clinicopathologic features of a distinctive type of mucosal polyp composed of cytologically bland spindled cells with fibroblastic features. Fourteen cases with histologic features of"fibroblastic polyps" were identified from our case files from January 2000 to December 2003. The clinical and endoscopic findings were reviewed. Immunohistochemistry using a panel of antibodies (vimentin, smooth muscle actin, desmin, CD31, CD34, Bcl-2, c-Kit, S-100, and epithelial membrane antigen) was performed in all cases, and electron microscopy was performed in two cases. The lesions were solitary in all cases and not associated with an identifiable polyposis syndrome. Associated adenomata and/or hyperplastic polyps at different sites were present in 10 cases and hyperplastic polyps were seen in close association in 3 cases. These polyps were characterized by a monomorphic spindle cell proliferation in the lamina propria, without necrosis or mitotic activity. The lesions were intimately associated with the muscularis mucosae and resulted in wide separation and disorganization of the colonic crypts. Immunohistochemical analysis revealed strong and diffuse positivity for vimentin only. Weak and focal reactivity was noted in 2 cases for CD34 and smooth muscle actin, while staining for other antibodies was negative. Electron microscopy revealed sparse cytoplasmic organelles and many intermediate filaments. The histology and ultrastructural and immunohistochemical findings are suggestive of fibroblastic differentiation of these spindle cells. In summary, these lesions represent a distinctive type of colonic mucosal polyp that should be distinguished from other stromal polyps of the gastrointestinal tract.
 ...
PMID:Benign fibroblastic polyps of the colon: a histologic, immunohistochemical, and ultrastructural study. 1537 61

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1(+) c-Kit(+) Lin(-)) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.
 ...
PMID:Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors. 1522 21

NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in beta selection checkpoint enforcement. At 5-8 wk of age, even in the absence of TCRbeta expression, CD4+ and CD4+CD8+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NODxB6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the beta selection program. They mimic normal beta selection by up-regulating germline TCR-Calpha transcripts, CD2, and Bcl-xL and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Ralpha. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRbeta rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.
 ...
PMID:Deranged early T cell development in immunodeficient strains of nonobese diabetic mice. 1549 84

Stem cell factor (SCF) is essential for the development of primordial follicles. One of its functions is to prevent oocytes from apoptosis. However, the underlying mechanism remains largely unknown. By using cultured ovaries that are rich in primordial follicles, the anti-apoptotic action of SCF and the potential signal transduction pathways were investigated. The apoptosis was evaluated by means of in situ 3'-end labeling. The expressions of proteins were analyzed with immunohistochemistry and Western blot. The data showed that SCF significantly prevented oocytes from apoptosis in the cultured organs. Addition of a specific pharmacological inhibitor of PI3K abolished the anti-apoptotic action of SCF while that of a MEK inhibitor did not. The phosphorylation of two mitogen activated protein kinases (MAPKs) (p42 and p44) and AKT, the respective substrates of MEK and PI3K, were enhanced by SCF treatment. Not surprisingly, the MAPK activation occurred only in theca cells. The expressions of apoptosis-related gene products, the Bcl-2 family proteins, in response to SCF treatment were also investigated. While SCF up-regulated the expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, it did the opposite to the pro-apoptotic factor Bax. The PI3K inhibitor reversed the regulation of SCF on Bcl-xL and Bax but not on Bcl-2. Therefore, it seemed that SCF initiated an anti-apoptotic signal starting from its membrane receptor c-kit to Bcl-2 family members through PI3K/AKT and other signaling cascades in the oocytes of primordial follicles.
 ...
PMID:Anti-apoptotic action of stem cell factor on oocytes in primordial follicles and its signal transduction. 1551 61

The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and c-kit oncoproteins.
 ...
PMID:Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. 1589 28

Improvements in conventional cytotoxic treatment have probably reached a plateau for the treatment of lung cancer; therefore, new treatment strategies that are based on a better understanding of tumour biology are required. Some progress has been made for non-small cell lung cancer, in which erlotinib (Tarceva, OSI-774; Genentech), an epidermal growth factor receptor antagonist, has demonstrated a significant clinical benefit in a Phase III randomised trial, and has been licensed for second- or third-line treatment. Other therapies under investigation include angiogenesis inhibitors, COX-2 inhibitors, retinoids, farnesyl transferase inhibitors, Bcl-2 inhibitors and c-Kit antagonists. In this article the recent and ongoing Phase II and III trials of these therapies in lung cancer are summarised, and the prospects for their further clinical development are discussed.
 ...
PMID:Perspectives on novel therapies for bronchial carcinoma. 1595 69

A 28-year-old woman presented with abdominal pain. Ultrasonograhic examination showed a pre-sacral mass, with complex structure and well delimitated cystss with thick walls. The resected specimen was 7.5 x 6 x 4 cm in size, well circumscribed and yellow in colour, with cysstic change containing mucoid-like material. Histologically, the lesion was composed of spindle cells with high cellularity and rich vascularization with a haemangiopericytoma-like pattern. The diagnosis of solitary fibrous tumour (SFT) was made. The differential diagnosis for SFT of the pre-sacral spaace involves haemangiopericytoma, GIST, malignant mesothelioma, synovial sarcoma, leiomyomatous tumours and granulosa cell tumour. Immunohistochemical studies revealed reactivity for CD34, CD99 and Bcl-2, but no staining for desmin, inhibin, c-kit, EMA, CK, SMA, S-100 and CD31, confirming a diagnosis of SFT. Although SFT is usually associated with a favourable prognosis, close follow-up is recommended because of the limited information on its long-term behaviour.
 ...
PMID:A rare case of solitary fibrous tumour of the pre-sacral space: morphological and immunohistochemical features. 1599 48

To identify the diagnostic pitfalls as well as the value of immunohistochemical studies in making a pathologic evaluation of a pediatric intestinal pseudo-obstruction (IPO), this study reassessed the pathology of 87 surgically resected intestines from 80 patients under the impression of IPO and 10 normal controls using immunohistochemical studies. The main diagnostic pitfall was the interpretation of the enteric nervous plexuses in the transitional zone and the detection of the indistinct or immature neurons indistinguishable from enteric glial cells or satellite cells. Immunohistochemical study was a very helpful diagnostic adjunct to delineating the immature neurons (bcl2), the size of the enteric ganglia and neuromuscular innervation (S-100 protein, synaptophysin, and CD56), and the interstitial cell of Cajal (c-Kit) and myopathy (SMA). With help of immunohistochemistry, our series of IPO could classify as neuropathy (92.5%), myopathy (2.5%), and the idiopathic forms (3.8%) more clearly. In terms of the types of neuropathy, Hirschsprung's disease (HD), pure hypoganglionosis, and intestinal neuronal dysplasia (IND-B) were diagnosed in 71.3%, 6.3%, and 48.8% of patients, respectively. IND-B was associated with other neuropathies, HD in 77.0% and hypoganglionosis in 7.7%, rather than being present in a pure form. Immature ganglion cells were found in 48.8%. Because a reduced number of interstitial cells of Cajal was commonly associated with HD in 84.2%, hypoganglionosis in 40%, and IND-B in 76.9% of cases, it might be a preceding or aggravating factor related to an IPO. In terms of detecting immature ganglion cells, we found bcl2 most helpful.
 ...
PMID:Immunohistochemical studies of pediatric intestinal pseudo-obstruction: bcl2, a valuable biomarker to detect immature enteric ganglion cells. 1686 87

Chemically modified tetracyclines are a group of non-antimicrobial tetracycline derivatives, which possess antiinflammatory, anticollagenolytic and antiproliferative properties. Here we studied the effects of four different chemically modified tetracyclines (CMT-1, CMT-3, CMT-8 and CMT-308) on proliferation and viability of cultured mouse and human mast cells. All studied CMTs (25 microM) effectively inhibited the viability and proliferation of human mast cell line (HMC-1) cells and mouse bone marrow derived mast cells (mBMMCs), as judged by trypan blue exclusion and by incorporation of [(3)H]thymidine. The antiproliferative effect of CMTs was not dependent on the stimulating growth factor, i.e. CMTs inhibited both IL-3 and c-kit ligand-induced proliferation of mBMMCs. The reduced viability of mast cells was due to induction of apoptosis, as indicated by the increased amount of apoptotic nucleosomes and the appearance of TUNEL positive cells in the presence of CMTs. The induction of apoptosis was further confirmed by showing that CMT-3 induces activation of caspase-3 and caspase-9 in HMC-1 cells. Additionally, CMT-3 induced downregulation of the expression of antiapoptotic Bcl-2 protein in HMC-1 cells. Compared to doxycycline, the antiproliferative and proapoptotic effects of different CMTs were clearly more pronounced. Of the studied CMTs, CMT-3 and CMT-8 appeared to be the most potent inhibitors of mast cell proliferation and survival. The present results show that CMTs have an antiproliferative and proapoptotic effect on both malignant and non-malignant mast cells. In conclusion, CMTs could offer a novel means to treat disorders with inappropriate expansion of mast cells, such as rheumatoid arthritis and systemic mast cell diseases.
 ...
PMID:Chemically modified tetracyclines induce apoptosis in cultured mast cells. 1603 51


<< Previous 1 2 3 4 5 6 7 Next >>