Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ras gene family of rodents and humans is highly conserved and consists of several distinct genes, i.e., rodent Harvey and Kirsten, and human Harvey, Kirsten and neuroblastoma. This gene family mediates transformation via (1) a point-mutation resulting in the change of one amino acid in the 21 kDA ras gene product (p21) or (2) increased expression of ras p21. Group-specific, type-selective and interspecies indirect binding liquid competition radioimmunoassays (RIAs), capable of providing truly quantitative analyses of the 21 ras oncogene and proto-oncogene products, have been developed. Using purified recombinant ras p21 from Escherichia coli expressing the full-length T24 mutant human Harvey-ras gene protein product as a standard in these RIAs, we have defined the absolute numbers of pg, fM and molecules of ras p21 in: (1) E. coli expressing the point-mutated or proto-ras p21 and (2) mammalian cell lines of human and murine origin. Two of the RIAs developed can be termed group-specific in that they have the ability to detect the point-mutated and proto forms of all 3 human ras genes (Harvey, Kirsten, and neuroblastoma), while the third RIA is type-selective, since it detects an antigenic determinant located primarily on the Harvey ras p21. All 3 RIAs are interspecies-specific since they are able to detect ras p21 in rodent as well as human cells. The adaptability of the RIAs to various assay conditions and ease of methodology make these immunoassays applicable to the study of several parameters associated with ras p21 expression. These assays, used in conjunction with specific cDNA probes to identify specific ras proto-oncogenes or point-mutated oncogenes being expressed, now provide truly quantitative analysis of ras p21 in mammalian cells to further the study of the association between ras p21 expression and transformation.
 ...
PMID:Development of quantitative liquid competition radioimmunoassays for the ras oncogene and proto-oncogene p21 products. 348 81

Several distinct and high-conserved genes comprise the ras gene family of rodents and humans, i.e., rodent Harvey and Kirsten, and human Harvey, Kirsten and neuroblastoma. Transformation, either by a point-mutation resulting in a change in one amino acid of the 21 kDa ras gene product (p21), or by increased expression of ras p21, has been demonstrated to be mediated by members of this gene family. We report here the development of direct binding liquid competition radioimmunoassays for the detection and quantitation of the ras oncogene and proto-oncogene products. Using these radioimmunoassays and ras p21 purified from Escherichia coli containing the full-length T24 mutant human Harvey ras gene protein product as a standard, we have defined the actual amount of ras p21 per micrograms of total cellular protein, or per cell, in various ras transformed and 'normal' mammalian cell lines. One of the radioimmunoassays developed is group-specific, since the antigenic determinant recognized is shared by both the point-mutated and proto-forms of Harvey, Kirsten and neuroblastoma members of the ras gene family, while the second may be termed type-selective, since it recognizes an antigenic determinant localized primarily on the Harvey ras p21. Both radioimmunoassays are interspecies, since they detect a ras p21 antigenic determinant common to cells of human and rodent origin. These studies thus describe the first means for defining absolute values of any oncogene or proto-oncogene protein product. The assays described, when used in combination with specific c-DNA probes to define specific ras proto-oncogenes or point-mutated oncogenes being expressed, will now permit truly quantitative analyses of ras p21 expression in experimental cell culture systems, animal models and human biopsy material.
 ...
PMID:Absolute values of ras p21 defined by direct binding liquid competition radioimmunoassays. 381

DNAS of some human tumours can transform NIH 3T3 fibroblast cells, thus demonstrating the transforming potential of human ras genes (Hu-rasHa, Hu-rasKi, and Hu-rasN, respectively Harvey, Kirsten and neuroblastoma ras genes). Only a small percentage of a given type of human carcinoma, however, scores positive in this assay system. Activation of ras and subsequent transformation of NIH 3T3 cells are either by a point mutation in the ras gene or enhanced expression of the normal, or proto-onc, ras gene. If the transformation of a given human tumour involves the enhanced expression of the normal or cellular ras gene and the resulting gene product, the tumour DNA would probably score negative in the NIH 3T3 transfection assay. In human colon carcinoma, for example, lesions at position 12 of Hu-rasKi have been found. None of nine colon carcinomas obtained at biopsy, however, contain the ras lesion at this position, using a Hu-rasHa probe; one other colon carcinoma does appear to contain amplified proto-onc ras, and other colon carcinomas do have increased levels of ras RNA. There are at least three explanations for these observations. Either very few colon carcinomas contain point-mutated ras, the lesion in the majority of colon carcinomas is at a position other than 12 or ras activation in many colon carcinomas involves the enhanced expression of either the point-mutated or proto-onc form of a ras gene. We have now used monoclonal antibodies directed against a synthetic peptide reflecting sequences of the human T24 ras gene product to define ras p21 protein expression in a spectrum of colonic disease states. Immunohistochemical analyses of individual cells within tissue sections reveal differences in ras p21 expression in colon carcinomas compared with normal colonic epithelium, benign colon tumours and inflammatory or dysplastic colon lesions. Our data suggest that ras p21 expression is correlated with depth of carcinoma within the bowel wall, and is probably a relatively late event in colon carcinogenesis.
 ...
PMID:Monoclonal antibodies define differential ras gene expression in malignant and benign colonic diseases. 648 68

We present three probands with partial trisomies 2p21-23 due to ins(4;2)(q21;p21p23) pat, 2p23-pter due to t(2;4)(p23;q35)mat, and 2p21-pter due to t(2;11)(p21;q23.3)mat. More than 50 cases of partial trisomy 2p have been reviewed and some abnormalities, unusual for most other types of structural autosomal imbalance, have been found in patients with inherited forms of 2p trisomy and in their non-karyotyped sibs. Neural tube defects (anencephaly, occipital encephalocele, and spina bifida) were found in five probands and 4/6 affected non-karyotyped sibs. The only triplicated segment common to all was 2p24. Different forms of "broncho-pulmonary a/hypoplasia" (including two cases of lung agenesis) were described in four patients (overlapping triplicated segment was 2p21-p25). Three patients (with overlapping triplicated segment 2p23-p25) had diaphragmatic hernia. Abnormal rotation of the heart or L-transposition of large vessels (with or without visceral heterotaxia) was found in two infants (overlapping triplicated segment 2p23-p24). In two patients with common triplicated segment 2p22.3-p25, neuroblastoma has been described. The occurrence of all these defects may be explained either by the action of the same gene(s) mapped to 2p24 or by action of some independent factors located in different segments of the short arm. Although the latter hypothesis is much less probable, it can not be rejected at the present time. We propose the existence of a genetic system controlling surveillance of an abnormal embryo to explain the phenotypic differences between patients with the same imbalance within a family. In some "restrictive" combinations the abnormal embryos will die, although in "permissive" combinations they can survive.
 ...
PMID:Trisomy 2p: analysis of unusual phenotypic findings. 771 24

Infants with neuroblastoma are known to have a favorable prognosis compared to those over 1 year of age. However, there is little biological information about the age-related heterogeneity of neuroblastoma. We evaluated the biological profile comparing cases detected by mass screening with those detected clinically. A total of 238 patients with neuroblastoma were classified into four groups according to their age at diagnosis. Patients in group A were 0-5 months of age (n = 31). Patients in group B were detected clinically and were 6-11 months of age (n = 25). Patients in group C were 6-11 months of age and were detected by mass-screening (n = 97). Patients in group D were more than 12 months of age (n = 85). The age-related heterogeneity was evaluated by Kaplan-Meier survival analysis, several clinical markers (neuron specific enolase, ferritin, vanillylmandelic acid and homovanillic acid) at diagnosis, tumor Ha-ras p21 expression and tumor N-myc amplification. Infant neuroblastoma had unique features in comparison to neuroblastoma diagnosed over 12 months of age. Clinical outcome of the patients in groups A and C was quite favorable. Even patients with stage III or IV disease in group A had a favorable prognosis. However, stage IVs disease in group A was not necessarily associated with a good prognosis and the early death after diagnosis was also characteristic. The biological profile of tumors in group C was similar to that in group A but different from the profile in groups B and D. Tumors in group B had a biological profile intermediate between groups A and D.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Age-related profile of neuroblastoma: a comparison of tumors detected by mass-screening with those detected clinically. 779 47

Thirty-six neuroblastomas were studied to determine the clinical significance of the N-myc gene product, N-myc, and the ras gene product, p21. The expressions of both gene products were analyzed immunohistochemically using formalin-fixed paraffin sections. Neuroblastoma cells were positive for N-myc expression in 13 cases and for p21 expression in 19 cases. N-myc expressions showed no significant relation to any clinical prognostic factor, whereas p21 expression was well correlated with clinical staging and Shimada's classification. There was a tendency for p21 expression to be low in N-myc(+) tumors, whereas p21 expression was frequently detected when N-myc expression was absent. The survival rate for N-myc(-) patients was significantly higher than for N-myc(+) patients (P < 0.01). The survival rate for p21(+) patients was significantly higher than for p21(-) patients (P < 0.001). In addition, N-myc(+) and p21(-) patients showed a strong tendency towards a poor prognosis, whereas a combination of p21(+) and N-myc(-) indicated a good prognosis (P < 0.01). The results suggest that expressions of N-myc and p21 detected by immunohistochemical staining could be among the most reliable prognostic indicators in neuroblastoma patients.
 ...
PMID:Expressions of N-myc and ras oncogene products in neuroblastoma and their correlations with prognosis. 835 Apr 88

n-Chimaerin is a GTPase-activating protein (GAP) mainly for Rac1 and less so for Cdc42Hs in vitro. The GAP activity of n-chimaerin is regulated by phospholipids and phorbol esters. Microinjection of Rac1 and Cdc42Hs into mammalian cells induces formation of the actin-based structures lamellipodia and filopodia, respectively, with the former being prevented by coinjection of the chimaerin GAP domain. Strikingly, microinjection of the full-length n-chimaerin into fibroblasts and neuroblastoma cells induces the simultaneous formation of lamellipodia and filopodia. These structures undergo cycles of dissolution and formation, resembling natural morphological events occurring at the leading edge of fibroblasts and neuronal growth cones. The effects of n-chimaerin on formation of lamellipodia and filopodia were inhibited by dominant negative Rac1(T17N) and Cdc42Hs(T17N), respectively. n-Chimaerin's effects were also inhibited by coinjection with Rho GDP dissociation inhibitor or by treatment with phorbol ester. A mutant n-chimaerin with no GAP activity and impaired p21 binding was ineffective in inducing morphological changes, while a mutant lacking GAP activity alone was effective. Microinjected n-chimaerin colocalized in situ with F-actin. Taken together, these results suggest that n-chimaerin acts synergistically with Rac1 and Cdc42Hs to induce actin-based morphological changes and that this action involves Rac1 and Cdc42Hs binding but not GAP activity. Thus, GAPs may have morphological functions in addition to downregulation of GTPases.
 ...
PMID:The GTPase-activating protein n-chimaerin cooperates with Rac1 and Cdc42Hs to induce the formation of lamellipodia and filopodia. 875 65

Several unique features of neuroblastoma (NB), including the capacity for spontaneous regression and maturation to benign pathology, suggest that genes that regulate cellular proliferation, survival and differentiation may be involved in directing clinical tumour aggressiveness. The in situ expression of Bcl-2, Rb, p21, p53 and Bax proteins, as well as the proliferation marker proliferating cell nuclear antigen (PCNA) were examined immunocytochemically in a selection of 38 stage- and outcome-identified NB tumours. Apoptotic cells were identified morphologically and by a DNA fragmentation labelling technique (TUNEL). Although the tumour cell density of Bcl-2, p53, Bax, PCNA and TUNEL positivity correlated with patient survival, a spatially organized expression pattern was further recognized in stroma-poor differentiating tumours. Immature tumour cells adjacent to thin fibrovascular stroma are proliferating, as evidenced by PCNA positivity, and often express Bcl-2. At increasing distance from this fibrovascular stroma, intermediately differentiated tumour cells express Rb, while with more advanced differentiation, proliferation ceases and Bcl-2 immunoreactivity is lost. The most differentiated tumour cells, which often express p53, and occasionally p21 and Bax, lie adjacent to TUNEL-positive, morphologically apoptotic cells. This spatial organization in favourable outcome NB tumours suggests that physiological regulation of differentiation and apoptosis may be involved in tumour regression.
 ...
PMID:Spatial association of apoptosis-related gene expression and cellular death in clinical neuroblastoma. 909 68

The p21 protein inhibits the activity of cyclin-Cdk complexes and suppresses cell cycle progression. Wild type p53 can induce p21, but mutated p53 cannot. Previous studies have demonstrated that mutation of p53 is absent in neuroblastoma (NB). These reports prompted us to examine whether p53 induced p21 in NB. We examined the expression of p21 and p53 mRNA in eight NB, two Ewing's sarcoma (ES) and two primitive neuroectodermal tumor (PNET) cell lines by Northern blot analysis, and sequenced p53 cDNA of these cells. Although p53 mRNA was detected in all analyzed cell lines by Northern blot analysis, p21 mRNA was detected in six NB but not in two NB, two ES and two PNET cell lines. We detected the point mutation of p53 at codon 273 (CGT to TGT) in one NB and two ES cell lines. The non-transforming substitution at codon 72 (CCC to CGC) was detected in all analyzed cell lines. One PNET cell line had a large deletion of p53 cDNA. These results showed that p21 mRNA was usually expressed in NB but not in ES and PNET. This may suggest that the down stream of the p53 signal transduction pathway in NB is different from that of the closely related tumors of ES and PNET.
 ...
PMID:p21 (WAF1/Cip1/Sdi1/Pic1) mRNA is expressed in neuroblastoma cell lines but not in Ewing's sarcoma and primitive neuroectodermal tumor cell lines. 936 58

Neuroblastomas show remarkable biological heterogeneity, resulting in favourable prognosis or unfavourable prognosis due to aggressive growth despite multimodal therapy. Recently, we proposed that aggressive tumours express telomerase at a high level while the favourable tumours lack or have low telomerase expression. To evaluate the correlation between telomerase activity and other biological characteristics reported as prognostic markers (MYCN gene amplification, loss of heterogeneity (LOH) in the short arm of chromosome 1, trk-A expression, Ha-ras p21 expression, and DNA ploidy), we investigated these biological features in 105 untreated neuroblastomas. In these cases, 23 showed high telomerase activity, 78 showed low activity, and telomerase activity was undetectable in 4 cases. Most tumours with genetic alterations (MYCN amplification or 1p32 LOH) showed high telomerase activity. Most tumours with low or undetectable activity were aneuploid, and showed trk-A and Ha-ras expression. Three of the four tumours with undetectable telomerase activity regressed. In 2 of the tumours with low telomerase activity, the residual tumours maturated and showed repression of telomerase activity. Thus, the level of telomerase activity correlated with other genetic alterations and/or gene expression and may be a useful prognostic indicator in neuroblastoma.
 ...
PMID:Telomerase activity in neuroblastoma: is it a prognostic indicator of clinical behaviour? 951 27


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