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)

Congenital melanocytic nevi (CMN) occur in 1% to 2% of newborns, and the risk of malignant melanoma is increased in patients with large CMN. Appearance at birth or later of a nodular or hyperpigmented area within a CMN simulates malignant melanoma and prompts biopsy. Although their clinical and pathologic features seem ominous, proliferative nodules (PNs) typically are benign and may regress, although atypical features cause greater concern. Here we report clinical and pathologic findings with outcome in 10 children who had multiple biopsies of large CMN with PNs. We reviewed 78 separate samples from the 10 patients and classified the 60 PNs according to published criteria. A subset of 30 samples containing both the CMN and a PNs was analyzed for immunohistochemical reactivity for melanocytic (S-100 protein, HMB45, melan-A), lymphocytic (CD45), cell-cycle/proliferative (Mib-1, p16, p21, p27, c-Myc), apoptotic (p53, Bax, c-kit, CD95), and anti-apoptotic (bcl-2) markers. Both CMN and PNs had similar expression of melanocytic, lymphocytic, and most cell-cycle/proliferative and apoptotic markers, including Mib-1, p16, p21, p27, c-Myc, Bax, CD95, and bcl-2. A greater proportion of PNs than CMN were reactive for p53 (67% vs. 30%, P < 0.0098) and c-kit (97% vs. 3%, P < 0.0001). p53 and p21 expression in CMN and all types of PNs were inversely correlated. When ordinary and atypical PNs were compared, the atypical PNs more frequently expressed p53, Mib-1, Bax, and bcl-2, but less frequently expressed p21. The c-kit expression in nearly all PNs and its absence in nearly all CMN is potentially useful for recognition of PN, suggests a delayed melanocytic maturation process in proliferative nodules, and may be likely indicative of their benign nature. p53 reactivity in concert with a lack of p21 up-regulation by immunohistochemistry suggests that a p53 mutation may be present in PN, although the immunohistochemical findings alone cannot exclude possible overexpression of wild-type p53. Regressive, involutional, or maturational changes were observed in sequential samples from 4 patients. No patient developed malignant melanoma or another melanocytic nevus-associated malignancy during the follow-up period. These findings underscore the similarities between PNs and the underlying CMN and suggest that maturational, proliferative, and apoptotic processes are involved in their clinical evolution.
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PMID:Proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. 1525 7

In the thymus, 2 types of Lin-Sca-1+ (lineage-negative stem cell antigen-1-positive) progenitors can generate T-lineage cells: c-Kit(hi) interleukin-7 receptor alpha-negative (c-Kit(hi)IL-7Ralpha-) and c-Kit(lo)IL-7Ralpha+. While c-Kit(hi)IL-7Ralpha- progenitors are absent, c-Kit(lo)IL-7Ralpha+ progenitors are abundant in the lymph nodes (LNs). c-Kit(lo)IL-7Ralpha+ progenitors undergo abortive T-cell commitment in the LNs and become arrested in the G1 phase of the cell cycle because they fail both to up-regulate c-myb, c-myc, and cyclin D2 and to repress junB, p16(INK4a), and p21(Cip1/WAF). As a result, development of LN c-Kit(lo)IL-7Ralpha+ progenitors is blocked at an intermediate CD44+CD25lo development stage in vivo, and LN-derived progenitors fail to generate mature T cells when cultured with OP9-DL1 stromal cells. LN stroma can provide key signals for T-cell development including IL-7, Kit ligand, and Delta-like-1 but lacks Wnt4 and Wnt7b transcripts. LN c-Kit(lo)IL-7Ralpha+ progenitors are able to generate mature T cells when cultured with stromal cells producing wingless-related MMTV integration site 4 (Wnt4) or upon in vivo exposure to oncostatin M whose signaling pathway intersects with Wnt. Thus, supplying Wnt signals to c-Kit(lo)IL-7Ralpha+ progenitors may be sufficient to transform the LN into a primary T-lymphoid organ. These data provide unique insights into the essence of a primary T-lymphoid organ and into how a cryptic extrathymic T-cell development pathway can be amplified.
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PMID:T-cell generation by lymph node resident progenitor cells. 1574 78

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.
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PMID:Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. 1608 54

Phyllodes tumors of the breast are rare biphasic tumors with the potential for invasion and metastatic spread. An important role of the epidermal growth factor receptor (EGFR) in phyllodes tumors has been proposed. However, detailed pathogenetic mechanisms remained unclear. We investigated 58 phyllodes tumors of the breast (40 benign, 10 borderline and eight malignant) by means of egfr fluorescence in situ hybridization (FISH) and gene dosage PCR for a regulatory sequence within intron 1 of egfr. Immunohistochemical staining was performed for EGFR, p16, p21, p27, p53, c-myc, Cyclin A, Cyclin D1, Cyclin E, c-kit and Ki67. Immunopositivity for EGFR was detected in 19% of phyllodes tumors (75% of all malignant tumors) in stromal tumor cells but not in the epithelial component. Whole-gene amplifications were seen by FISH in 15.8% (in stromal cells only) and intron 1 amplifications by gene dosage PCR in as much as 41.8% of all phyllodes tumors. Significant correlations were seen between tumor grade on the one hand and EGFR overexpression (P=0.001) and intron 1 amplifications (P<0.05) on the other. EGFR overexpression further correlated positively with immunohistochemical staining for p53, p16, Cyclin A, Cyclin E, Ki67 and c-kit. Presence of intron 1 amplifications correlated with p16 (P<0.01), p21 (P=0.009) and p53 immunoreactivity (P<0.001). Neither EGFR overexpression nor whole-gene amplification was observed in a control series of 167 fibroadenomas and only one of 43 (2.3%) exhibited intron 1 amplification in gene dosage PCR. In conclusion, our results show for the first time that activating mutations in and overexpression of egfr are associated with the progression in grade of phyllodes tumors of the breast. The observed association between intron 1 amplification and overexpression of EGFR provides further insight into regulation mechanisms of EGFR overexpression.
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PMID:Amplifications of the epidermal growth factor receptor gene (egfr) are common in phyllodes tumors of the breast and are associated with tumor progression. 1625 23

We have studied sarin-induced global gene expression patterns at an early time point (2 h: 0.5 x LD50) using Affymetrix Rat Neurobiology U34 chips and male Sprague-Dawley rats. A total of 46 genes showed statistically significant alterations from control levels. Three gene categories contained more of the altered genes than any other groups: ion channel (8 genes) and calcium channel and binding proteins (6 genes). Alterations were also found in the following gene groups: ATPases and ATP-based transporters (4), growth factors (4), G-protein-coupled receptor pathway-related molecules (3), neurotransmission and neurotransmitter transporters (3), cytoskeletal and cell adhesion molecules (2), hormones (2), mitochondria-associated proteins (2), myelin proteins (2), stress-activated molecules (2), cytokine (1), caspase (1), GABAnergic (1), glutamergic (1), immediate early gene (1), prostaglandin (1), transcription factor (1), and tyrosine phosphorylation molecule (1). Persistent alteration of the following genes also were noted: Arrb1, CaMKIIa, CaMKIId, Clcn5, IL-10, c-Kit, and Plp1, suggesting altered GPCR, kinase, channel, and cytokine pathways. Selected genes from the microarray data were further validated using relative RT-PCR. Some of those genes (GFAP, NF-H, CaMKIIa, Calm, and MBP) have been shown by other laboratories and ours, to be involved in the pathogenesis of sarin-induced pathology and organophosphate-induced delayed neurotoxicity (OPIDN). Induction of both proapoptotic (Bcl2l11, Casp6) and antiapoptotic (Bcl-X) genes, besides suppression of p21, suggest complex cell death/protection-related mechanisms operating early on. Principal component analysis (PCA) of the expression data confirmed that the changes in gene expression are a function of sarin exposure, since the control and treatment groups separated clearly. Our model (based on current and previous studies) indicates that both degenerative and regenerative pathways are activated early and contribute to the level of neurodegeneration at a later time, leading to neuro-pathological alterations.
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PMID:Toxicogenomic studies of the rat brain at an early time point following acute sarin exposure. 1673 13

Stem cells have been identified as essential for maintaining multiple organ systems, including the hematopoietic system. The distinct cell fates of self-renewal and differentiation of hematopoietic stem cells (HSCs) depend on cell division. Recently, several negative regulators of the cell cycle, such as the cyclin-dependent kinase inhibitors p21(Cip1), p27(Kip1), and p16(INK4a)/p19(ARF), have been demonstrated to have a role in regulating HSC fate decisions, suggesting that regulation of the G(1)-S phase transition can contribute to HSC self-renewal. Because the retinoblastoma protein, Rb, plays a central role in the regulation of the G(1)-S phase cell cycle, we sought to determine whether it has an intrinsic role in the regulation of HSC fate. Surprisingly, we found that HSC function was essentially normal in the absence of Rb. Rb(Delta/Delta) HSCs contributed normally to both myeloid and lymphoid lineages in both primary and secondary recipients, and no evidence of transformation was observed. Additionally, we observed a mild myeloid expansion and decrease in mature B cells within the Rb(Delta/Delta) bone marrow but a similar contribution to phenotypic HSC populations compared with nondeleted bone marrow. The Rb family members p107 and p130 were not deregulated in cells in which Rb had been deleted, as determined by quantitative RT-PCR on the highly enriched stem and primitive progenitor cell lin(-)c-Kit(+)Sca-1(+) population. These studies demonstrate that Rb is not intrinsically required for self-renewal and multilineage differentiation of adult HSCs.
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PMID:Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells. 1675 50

Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss of hematopoietic stem cell function was associated with decreased expression of Cdkn1a (encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 (encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1 was upregulated in erythroid progenitors. Constitutive activation of canonical Wnt signaling therefore causes multilineage differentiation block and compromised hematopoietic stem cell maintenance.
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PMID:Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. 1698 97

In order to define genetic determinants of primary and metastatic melanoma cell susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we have applied oligonucleotide microarrays to TRAIL-sensitive primary T1 cells and TRAIL-resistant metastatic G1 cells treated or not with TRAIL. T1 and G1 cells are isogenic melanoma cell subclones. We examined 22 000 spots, 4.2% of which displayed differential expression in G1 and T1 cells. Cell susceptibility to TRAIL-mediated apoptosis was found to be correlated with gene expression signatures in this model. Some of the differentially expressed genes were identified as involved in ATP-binding and signaling pathways, based on previously published data. Further analysis provided evidences that c-kit was overexpressed in G1 cells while it was absent in T1 cells. The c-kit inhibitor, imatinib, did not restore TRAIL sensitivity, excluding a role for c-kit in TRAIL resistance in G1 cells. Surprisingly, imatinib inhibited cell proliferation and TRAIL-mediated apoptosis in melanoma cells. We investigated the possible involvement of several molecules, including c-ABL, platelet-derived growth factor receptor (PDGFR), cellular FADD-like interleukin-1 alpha-converting enzyme-like inhibitory protein (c-FLIP)(L/S), Fas-associated DD kinase, p53, p21(WAF1), proteins of B-cell leukemia/lymphoma 2 (Bcl-2) family and cytochrome c. Imatinib did not modulate the expression or activation of its own targets, such as c-ABL, PDGFRalpha and PDGFRbeta, but it did affect the expression of c-FLIP(L), BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIP(L) knockdown sensitized T1 cells to TRAIL-mediated apoptosis, with a sensitivity similar to that of cells previously treated with imatinib. More notably, we found that the resistance to TRAIL in G1 cells was correlated with constitutive c-FLIP(L) recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIP(L) knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIP(L) and its interaction with TRAIL receptor2 play a crucial role in determining TRAIL resistance in metastatic melanoma cells. Our results also show that imatinib enhances TRAIL-induced cell death independently of BH3-interacting domain death agonist translocation, in a process involving the Bax:Bcl-X(L) ratio, Bax:Bcl-X(L)/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIP(L), with the use of an alternative pathway for antitumor activity, because PDGFRalpha is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRbeta. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL.
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PMID:Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: Relationship to Bcl-2 family and caspase activation. 1698 47

Sebaceous lesions, including sebaceous hyperplasia, sebaceomas, and sebaceous adenomas and carcinomas, are histologically distinctive adnexal proliferations with a spectrum of biological behavior ranging from benign to frankly malignant. The histologic distinction between sebaceous adenomas and carcinomas may be challenging, especially in cases showing atypical features and in small or partial biopsies. We studied multiple oncogenic and therapeutic related proteins by immunohistochemistry to identify differences in expression between benign and malignant sebaceous proliferations. A total of 27 cases, including 9 sebaceous adenomas, 4 sebaceomas, 8 sebaceous carcinomas, and 6 cases of sebaceous hyperplasia, were examined by immunohistochemistry, with antibodies directed against Ki-67 (MIB-1), bcl-2, p53, p21WAF1, p27Kip1, c-erbB-2 (Her-2/neu), CD117 (c-kit), cyclin D1, MDM2, CD99, MLH-1, and MSH-2. We found that sebaceous adenomas and sebaceomas stained like sebaceous hyperplasia did, whereas carcinomas had statistically significantly increased levels of p53 (50% versus 11%, respectively) and Ki-67 (30% versus 10%). The carcinomas also had significantly reduced levels of bcl-2 (7% versus 56%, respectively) and p21 (16% versus 34%) compared to the adenomas. Thus, a combination of several of these markers may be diagnostically useful in challenging cases. In addition, we found little or no Her-2/neu and CD117 staining, indicating that immunotherapy with Herceptin or Gleevac would likely not be useful for sebaceous carcinomas. Moreover, these results show that sebaceous adenomas and carcinomas are distinct neoplasms and provide no support for the theory that all sebaceous adenomas are truly malignant.
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PMID:Distinction of benign sebaceous proliferations from sebaceous carcinomas by immunohistochemistry. 1712 89

Several studies have suggested that the cyclin-dependent kinase (CDK) inhibitor p21 plays a crucial role in regulating hematopoietic stem and progenitor pool size. To allow assessment of long-term stem cell functioning in vivo, we have backcrossed a p21 null allele to C57BL/6 (B6) mice, the most commonly used mouse strain in hematopoietic stem cell research. In various in vitro assays, the homozygous deletion of the p21 allele did not affect the number of hematopoietic cells in B6 mice. Furthermore, the competitive repopulation ability was not different between p21-deficient and wild-type stem cells from both young and aged (20-month-old) mice. These results show that p21 is not essential for regulation of stem cell number in steady state. When proliferative stress was applied on p21-deficient stem cells by serial transplantation of 1,500 Lin(-)Sca-1(+)c-kit(+) (LSK) cells, again no detrimental effect was observed on cobblestone area-forming cell (CAFC) frequency and competitive repopulating ability. However, when bone marrow cells from mice that received 2 Gy of irradiation were transplanted, p21 deficiency resulted in a more than fourfold reduction in competitive repopulation index. Finally, we did not find major differences in cell cycle status and global gene expression patterns between LSK cells from p21-deficient and wild-type mice. Our findings indicate that the background of mice used for studying the function of a gene by genetic modification may determine the outcome. Cumulatively, our data fail to support the notion that p21 is essential for stem cell function during steady-state hematopoiesis, but may be relatively more important under conditions of cellular stress.
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PMID:A Limited role for p21Cip1/Waf1 in maintaining normal hematopoietic stem cell functioning. 1717 62


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