Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

gamma-Synuclein is a small cytoplasmic protein implicated in neurodegenerative diseases and cancer. However, the mechanism of its involvement in diseases is not clear. We studied the role of gamma-synuclein in the regulation of matrix metalloproteinases in retinoblastoma cell culture. Matrix metalloproteinases play important roles in the remodeling of extracellular matrix implicated in tumor progression and in the neurodegenerative diseases. Western blot and zymography data demonstrated a moderate elevation of matrix metalloproteinases-2 and significant upregulation of matrix metalloproteinases-9 in stable cell lines overexpressing gamma-synuclein. No effect of gamma-synuclein overexpression on matrix metalloproteinases-1 level or activity was found. Chloramphenicol-acetyltransferase assay demonstrated that overexpression of gamma-synuclein increases the efficiency of the matrix metalloproteinases-9 promoter. This increment of promoter activity may be mediated by the AP-1 binding site(s), since point mutations in one of these sites (Pr18 or Pr19) and elimination of the distal AP-1 site (Pr14) reduced the increment of promoter activity.
 ...
PMID:Effect of gamma-synuclein overexpression on matrix metalloproteinases in retinoblastoma Y79 cells. 1255 90

Gallbladder carcinomas can be highly lethal neoplasms. Relatively little is known about the genetic abnormalities that underlie these tumors, particularly with respect to their timing in neoplastic progression. The authors evaluated 5 noninvasive dysplasias and 33 invasive gallbladder carcinomas (6 small cell carcinomas, 27 non-small cell carcinomas, of which 16 were accompanied by an in situ carcinoma component) for expression of the protein products of the p16, p53, Dpc4, and pRB tumor suppressor genes by immunohistochemistry. Neoplasms were also evaluated for the presence of activating K-ras oncogene mutations. Seventy-five percent of non-small cell gallbladder carcinomas demonstrated loss of p16 expression, whereas 63% accumulated high levels of p53. Loss of Dpc4 and pRB expression was less frequent, seen in 19% and 4% of the neoplasms, respectively. Thirty percent of neoplasms harbored activating K-ras mutations. In contrast, 100% of the small cell carcinomas of the gallbladder demonstrated inactivation of the pRB/p16 pathway; 67% showed loss of pRB expression, and the other 33% lost p16 expression. Eighty-three percent of small cell carcinomas accumulated high levels of p53, whereas loss of Dpc4 expression and activating K-ras mutations were not found. Among 15 evaluable in situ components, 13 harbored the same alterations found in the invasive component. Inactivation of p16 and p53 occur in the majority of non-small cell gallbladder carcinomas. Dpc4 inactivation and K-ras mutations occur in a significant minority of cases. pRB loss is uncommon in non-small cell gallbladder carcinoma, but virtually all small cell carcinomas inactivate the p16/pRB pathway, usually by retinoblastoma protein loss. It is noteworthy that all of these alterations occur at the level of carcinoma in situ.
 ...
PMID:Immunohistochemical and genetic analysis of non-small cell and small cell gallbladder carcinoma and their precursor lesions. 1269 94

Autocrine motility factor (AMF)/phosphoglucose isomerase (PGI; EC 5.3.1.9) is a housekeeping cytosolic enzyme that plays a key role in both glycolysis and gluconeogenesis pathways. AMF/PGI is also a multifunctional protein that displays cytokine properties, eliciting mitogenic, motogenic, and differentiation activities, and has been implicated in tumor progression and metastasis. Because little is known about AMF/PGI-dependent signaling in general and during tumorigenesis in particular, we sought to study its effect on the cell cycle. To elucidate the functional role of PGI, we stably transfected its cDNA into NIH/3T3 and BALB/c 3T3-A31 fibroblasts. Ectopic overexpression of PGI results in the acquisition of a transformed phenotype associated with an acceleration of G1 to S cell cycle transition. These were manifested by up-regulation of cyclin D1 expression and cyclin-dependent kinase activity and down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. The reduced p27Kip1 protein expression level in PGI-overexpressing cells could be restored to control levels by treatment with proteasome inhibitor. PGI-overexpressing cells also exhibited elevated expression of Skp2 involved in p27Kip1 ubiquitination and elevation in the levels of retinoblastoma protein hyperphosphorylation. Thus, we may conclude that the overexpression of AMF/PGI enhances cell proliferation together with up-regulation of cyclin/cyclin-dependent kinase activities and down-regulation of p27Kip1, whereas the induction of 3T3 fibroblast transformation by PGI is regulated by the retinoblastoma protein pathway.
 ...
PMID:Regulation of cell proliferation by autocrine motility factor/phosphoglucose isomerase signaling. 1278 64

Cellular senescence is an extremely stable form of cell cycle arrest that limits the proliferation of damaged cells and may act as a natural barrier to cancer progression. In this study, we describe a distinct heterochromatic structure that accumulates in senescent human fibroblasts, which we designated senescence-associated heterochromatic foci (SAHF). SAHF formation coincides with the recruitment of heterochromatin proteins and the retinoblastoma (Rb) tumor suppressor to E2F-responsive promoters and is associated with the stable repression of E2F target genes. Notably, both SAHF formation and the silencing of E2F target genes depend on the integrity of the Rb pathway and do not occur in reversibly arrested cells. These results provide a molecular explanation for the stability of the senescent state, as well as new insights into the action of Rb as a tumor suppressor.
 ...
PMID:Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. 1280 2

Thymomas are thymic epithelial tumors. Because most of them are rich in nonneoplastic T-cells, recurrent genetic aberrations have been reported only in the rare, lymphocyte-poor WHO types A, B3, and C. We have now investigated virtually the whole spectrum of thymomas, including the commoner types AB and B2, microdissecting or culturing neoplastic cells from these lymphocyte-rich thymomas and applying 41 microsatellite markers covering 17 loci on 10 chromosomes. In 28 cases, comparative genomic hybridization data were available. Apart from type A, there was striking heterogeneity between thymomas. Allelic imbalances were seen in 87.3% of the 55 cases, and MSI in 9.9%. Losses of heterozygosity (LOHs) were much the commonest aberration. Overall, they were most prevalent at four regions on chromosome 6. Aberrations elsewhere, affecting mainly 8p11.21 and 7p15.3, suggested a cortical footprint because they recurred only in the thymopoietically active type AB and B thymomas. LOHs were also seen at the adenomatous polyposis coli (APC) locus (5q21-22) in subsets of these thymomas, whereas combined LOHs at the APC, retinoblastoma (13q14.3), and p53 (17p13.1) loci were confined to a subset of B3 thymomas that had possibly evolved from APC-hemizygous B2 thymomas by tumor progression; indeed, thymomas combing B2 plus B3 features are common. Notably, some AB and B thymomas shared LOHs despite their nonoverlapping morphology and different clinical behavior. Finally, allelic imbalances at 8p11.21 and 16q22.1 (CDH1) were significantly more frequent in stage IV metastatic thymomas. We conclude that the WHO-defined histological thymoma types generally segregate with characteristic genetic features, type A thymomas being the most homogeneous. Many findings support the view that B2 and B3 thymomas form a continuum, with evidence of tumor progression. However, other findings imply that types A and AB are biologically distinct from the others, any potential invasiveness being severely restricted by a medullary commitment in the precursor cell undergoing neoplastic transformation.
 ...
PMID:Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. 1283 63

Genomic instability is thought to underlie tumor progression in solid tumors, such as breast cancer. Although evidence that the hereditary breast cancer genes, BRCA1 and BRCA2, are involved in DNA repair suggests that genomic instability plays an important role in hereditary breast tumorigenesis, genomic instability remains poorly characterized in sporadic breast cancers. Using a DNA fingerprinting technique, inter-(simple sequence repeat) PCR (inter-SSR PCR), the degree of genomic instability was quantified in 47 sporadic breast cancers compared with matched adjacent normal breast tissues. Almost all sporadic breast cancers show significant genomic instability by inter-SSR PCR. The distribution of this instability is bimodal; 57% of the tumors show fewer changes, whereas 43% show striking genomic alterations. Further analysis of two inter-SSR PCR tumor-normal differences revealed a genomic amplification and probable deletion. Thus, inter-SSR PCR can detect chromosomal breakage-related genomic alterations in most sporadic breast cancers. Genomic instability as detected by inter-SSR PCR is not correlated with aneuploidy, suggesting that this technique preferentially detects intrachromosomal alterations. Chromosomal instability in breast cancer can therefore be subdivided into at least two groups: (a) intrachromosomal and (b) gross chromosomal. Allelic imbalance at markers at the 13q13 and retinoblastoma loci (13q) and not at 17q loci was significantly associated with high levels of intrachromosomal instability, suggesting genes at 13q13 and retinoblastoma loci are either selectively targeted or involved in the genesis of genomic instability in sporadic breast cancers.
 ...
PMID:Widespread bimodal intrachromosomal genomic instability in sporadic breast cancers associated with 13q allelic imbalance. 1290 36

Id proteins are general inhibitors of differentiation and positive regulators of proliferation in the nervous system. The role of Id is especially evident in neural development, a period during which Id proteins prevent premature differentiation and terminal cell cycle arrest. These activities have been related to the recognized ability of Id proteins to antagonize basic helix loop helix transcription factors and proteins of the Retinoblastoma tumor suppressor family. In recent experiments, it was shown that Id proteins-normally low or absent in post-natal tissues-are abnormally expressed by tumor and endothelial cells of neoplasms derived from the central nervous system and peripheral nervous system. In these tumors, deregulated Id activity has been associated with relentless proliferation, loss of differentiation and neo-angiogenesis, all key features of neural tumor progression. Future work will be required to fully elucidate the molecular networks engaged by Id proteins to contribute to the essential hallmarks of neural cancer.
 ...
PMID:Id proteins in neural cancer. 1501 18

Multidrug resistance (MDR) to anticancer agents is a major barrier to the successful treatment of human osteosarcomas. Current understanding of the genes that contribute to the features of MDR is limited, and the mechanisms remain unclear. Here we applied differential display reverse transcription-polymerase chain reaction (DDRT-PCR) to parental and MDR-variants of U-2 OS human osteosarcoma cells, to clarify the genes involved in the MDR cells, and identified five candidate genes. These are BCRP (breast cancer resistance protein) encoding a transmembrane efflux pump; RB1CC1 (RB1-inducible coiled-coil 1), a tumor suppressor regulating RB1 (retinoblastoma 1) expression; a novel transcriptional variant of dUTPase; SSR2 (beta-signal sequence receptor), which is associated with protein translocation across ER membrane; and HSP105 encoding high molecular mass heat shock proteins. Molecular and biological characterization of these genes will yield further insight into the features between MDR and tumor progression in human osteosarcomas.
 ...
PMID:Differentially expressed genes in multidrug resistant variants of U-2 OS human osteosarcoma cells. 1513 64

The p73 gene is able to encode transcriptionaly active TAp73, as well as a dominant-negatively acting DeltaNp73 transcript isoforms. We studied differential expression of these forms in normal brain as well as glial tumors, by semiquantitative RT-PCR. The expression of p73 was low or undetectable in normal brain tissues. Most of the tumors and non-tumor brain tissues also lacked significant expression of p73 in patients with low-grade astrocytomas. In contrast, most high-grade glial tumors displayed strong up-regulation of TAp73, whereas only a few displayed DeltaNp73 expression. These aberrations may reflect the inactivation of retinoblastoma pathway in these tumors which result in the activation of E2F transcription factors, since TAp73 is a known target of E2F1 gene. The study of TAp73 expression in brain tumors may serve as a means to evaluate the retinoblastoma pathway-dependent tumor progression.
 ...
PMID:Expression of TAP73 and DeltaNP73 in malignant gliomas. 1513 75

Based on the concept that tumor suppressor genes are involved in the pathogenesis of urinary bladder carcinogenesis, we analysed the mRNA expression of the retinoblastoma (Rb) and p16 (CDKN2, INK4A, MTS1) genes as well as of the proto-oncogene cyclin D-dependent kinase 4 (CDK4) in 71 transitional cell carcinomas (TCC) of the urinary bladder in relation to the tumor grades and stages, and with reference to certain lifestyle and occupational risk factors. Using real-time quantitative reverse transcription-polymerase chain reaction, high-stage muscle invasive TCC expressed the Rb, p16 and CDK4 mRNA at lower levels than low-stage superficial cancers, indicating down-regulation to be linked with tumor progression. The drop of the expression in the group of grade 2 TCC when invading the muscle layer compared to grade 2 carcinomas with a superficial pattern of growth is considered to represent a key event in promoting urothelial carcinogenesis in this subset of carcinomas. The protein expression of the Rb gene evaluated by immunohistochemistry proved to be closely related to the tumor grades and stages as well as to the mRNA expression, high-grade and high-stage TCC disclosing a lower rate of positive immunoreactivity than low-grade and low-stage carcinomas. The p16 protein product was expressed at a lower level in grade 3 than in grade 1 TCC, but there was no correlation with the tumor stages or the mRNA expression. TCC with loss of heterozygosity (LOH) at the INK4A region showed a decreased expression of p16 mRNA compared to those without an allelic loss. Tobacco smoke was not identified to substantially modulate the Rb/p16/CDK4 pathways, except for a ten-fold elevated mRNA expression of the p16 gene in TCC of light compared to heavy smokers. Heavy coffee consumption was associated with a reduced expression of CDK4 mRNA. Among occupational exposures, TCC of patients in contact with stone dust, paints and lacquer, plastics, wood and wood preservers and chemical solvents and adhesives displayed altered partly elevated, partly reduced levels of Rb, p16 and CDK4 mRNA compared to non-exposed subjects. Although the underlying molecular-genetic pathways are not yet fully understood, the current results suggest functional reduction of the tumor suppressor genes Rb and p16 to be associated with progression of bladder cancer to a more malignant and aggressive behaviour.
 ...
PMID:Altered mRNA expression of the Rb and p16 tumor suppressor genes and of CDK4 in transitional cell carcinomas of the urinary bladder associated with tumor progression. 1516 Oct 57


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