Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Solid tumours in man are characterized by acquired genetic rearrangements that, in most cases, can be detected by cytogenetic methods as clonal chromosomal abnormalities. Whereas primary abnormalities contribute to the establishment of the tumour and often are seen as solitary changes, secondary aberrations accrue during clonal evolution. Both abnormalities are nonrandom in distribution. Some primary abnormalities are so characteristic as to be virtually pathognomonic for particular types of solid tumours, eg, t (11;22)(q24;q12) in Ewing's sarcoma, t (9,22)(q22;q12) in extraskeletal myxoid chondrosarcoma, t (X;18)(p11;q11) in synovial sarcoma, and t (12;16)(q13;p11) in myxoid liposarcoma. To these purely cytogenetic data implicating specific genetic changes in carcinogenesis may now be added a growing evidence of molecular specificity emerging from recombinant DNA-studies. It appears that both currently known classes of directly cancer-relevant genes, the dominant oncogenes and the recessive tumour suppressor genes, are located at precisely those genomic sites that are visibly involved in neoplasia-associated chromosomal rearrangements. The importance of cytogenetic characterization of solid tumors is thus twofold. First, the recurrent aberrations provide insight into the pathogenetic mechanisms that are operative. They pinpoint areas of the human genome that carry genes or regulatory sequences whose function is disrupted in neoplastic cells. Second, even before the long-term goal of a more fundamental understanding of the neoplastic process is reached, the cytogenetic aberrations have direct clinical importance. The finding of an acquired clonal chromosomal abnormality identifies the presence of a neoplastic disease, and the specific type of aberration may reveal the true nature of the tumor and thus improve the diagnostic precision.
 ...
PMID:[Significance of chromosomal abnormalities in solid tumors of humans]. 817 15

Alterations of tumour suppressor genes are considered crucial steps in the development of human cancers. Expressions of p53 protein, a product of the tumour suppressor gene altered most commonly in human cancers examined so far, were investigated immunohistochemically in 18 osteosarcomas and 40 other malignant and benign lesions of bone. A monoclonal antibody clone PAb240, which recognizes a common conformational epitope of mutant p53 proteins, stained nuclei of tumour cells in 12 of 18 osteosarcomas (67%). Six tumours (33%) particularly showed positive immunoreactions in more than half of the tumour cells. PAb240 also stained tumour cells in a small number of other malignant bone tumours, such as malignant fibrous histiocytoma, chondrosarcoma, and Ewing's sarcomas. Furthermore, a small number of cells of giant-cell tumours were positively stained. In contrast, PAb240 was completely negative in 21 benign bone tumours and reactive lesions examined. Another monoclonal antibody clone PAb1801, which reacts with both wild- and mutant-type p53 protein, reacted in nuclei of tumour cells of 7 osteosarcomas (39%). Most of those also reacted with PAb240. PAb1801 was expressed much more frequently in other malignant bone tumours and giant-cell tumours. In addition, PAb1801 showed intranuclear positive reactions in tumour cells of a benign chondroblastoma, and reactive cells such as actively proliferating preosteoblasts in a myositis ossificans and osteoclast-like giant cells in a giant-cell tumour. The immunoelectron-microscopic observation that p53 protein was localized in euchromatic areas of nuclei of osteosarcoma cells supported the specificity of immunoreaction for p53 protein, indicating an active role of p53 protein in the regulation of DNA synthesis and transcription. These findings suggest that point mutation of the p53 gene is frequently involved in the development of osteosarcomas. PAb240 may be a useful tool not only in screening point mutations of the p53 gene in osteosarcomas but also in the differential diagnosis between osteosarcomas and reactive bone-forming lesions. Expressions of mutant p53 protein were not correlated with any clinical or pathological factors examined, although the results should be confirmed in studies of a large number of osteosarcomas.
 ...
PMID:Analysis of mutant P53 protein in osteosarcomas and other malignant and benign lesions of bone. 841 91

Many theories of osteochondroma pathogenesis have been advanced. Genetic research into the inherited multiple form, hereditary multiple exostoses, has revealed a new family of tumour suppressor genes denoted EXT. Patterns of EXT gene mutation in hereditary multiple exostoses, in solitary and multiple osteochondromas, and in chondrosarcoma are analogous to those found in other tumour suppressor genes responsible for family cancer traits and associated malignancies. With one exception, most features of osteochondroma behaviour are comparable to those of benign neoplasms. The neoplastic pathogenesis of osteochondromas provides an alternative to the traditional 'skeletal dysplasia' theory to explain the growth disturbance associated with hereditary multiple exostoses. Recent studies on the physiological function of EXT genes are reviewed and implications for osteochondroma 'cell-of-origin' theories are discussed.
 ...
PMID:The neoplastic pathogenesis of solitary and multiple osteochondromas. 1070 4

The role of two important tumour suppressor genes, p16 and p53, was evaluated in cartilaginous tumour tissues. Genomic DNA from 22 chondrosarcomas, 5 benign chondroid tumours, 1 sample of reactive proliferative cartilage and 2 samples of normal cartilage were analysed using polymerase chain reaction, single strand conformational polymorphism, DNA sequencing and methylation-specific polymerase chain reaction. The p16 gene was found to be partly methylated in 5 high-grade chondrosarcomas and homozygously deleted in 1 chondrosarcoma. Moreover, a polymorphism was detected in 3 malignant tumours, but not in benign tumours or normal cartilage. Analysis of the p53 gene revealed an unchanged structure in all samples. These findings show a role for p16, but not p53, in chondrosarcoma.
 ...
PMID:Changes of the p16 gene but not the p53 gene in human chondrosarcoma tissues. 1070 95

Both the tumour suppressor, p16, and the helix-loop-helix transcription factor, Id1, have been assigned roles in tumour growth in general and appear to be involved in chondrosarcoma. Id1 has further been found to repress the expression of p16. Therefore, the mRNA expression of these two genes was studied by real-time PCR in a search for prognostic markers in human chondrosarcoma. To get reliable quantitative data, however, the choice of endogenous reference gene for use in the assay is important. Therefore, eleven different endogenous reference genes were evaluated in chondrosarcoma cells and articular chondrocytes. 18S rRNA appeared to be the best choice to use as endogenous reference gene, since it was suitable for both kinds of cells. Several of the other reference genes tested showed variation between individuals or between normal chondrocytes and chondrosarcoma cells. This demonstrates the importance of using a correct endogenous reference gene to get reliable results from quantitative measurements. Both p16 and Id1 showed varied gene expression patterns among the samples and none of these genes could be significantly correlated to prognosis.
 ...
PMID:Evaluation of p16 and Id1 status and endogenous reference genes in human chondrosarcoma by real-time PCR. 1627 14

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and it seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities, especially of the forearm, that may be reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5%. MO is an autosomal dominant disorder and is genetically heterogeneous. In almost 90% of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization. The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of osteochondromas. If the exact mutation is known antenatal diagnosis is technically possible. MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease. Osteochondromas are benign lesions and do not affect life expectancy. Management includes removal of osteochondromas when they give complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins, preferably in a bone tumour referral centre, should be performed.
 ...
PMID:Multiple osteochondromas. 1827 66

Hereditary multiple exostoses (HME) is an autosomal-dominant disorder characterized by the development of benign tumours, multiple osteochondromas (exostoses), growing outward from the metaphyses of long bones. Birth prevalence is estimated to be one in 50,000, and the severity of the disease is variable. Osteochondromas may cause complications including pain, deformities and shortening of the long bones, restricted motion of joints, nerve or blood vessel compression, and malignant transformation (5% of cases) in adulthood. HME is a genetically heterogeneous disorder and is associated with mutations in EXT1 or EXT2 genes, which are both tumour suppressor genes. EXT genes encode glycosyltransferases, termed 'exostosins', which are involved in the biosynthesis of heparan sulphate. Enchondromatosis (or Ollier disease) is characterized by the presence of intra-osseous benign cartilaginous tumours. The estimated prevalence of the disease is one in 100,000. An asymmetrical distribution of cartilage lesions is observed in the disease. The number, size and location of the enchondromas can be extremely variable between patients. Clinical problems caused by enchondromas include skeletal deformities, limb length discrepancy, pain and the potential risk for malignant change to chondrosarcoma (20-50% of cases). The condition in which multiple enchondromas is associated with haemangiomas is known as 'Maffucci syndrome'. Ollier disease and Maffucci syndrome are not usually inherited disorders.
 ...
PMID:Hereditary multiple exostoses and enchondromatosis. 1832 80

Multiple Osteochondromas is an autosomal dominant disorder characterised by the presence of multiple osteochondromas and a variety of orthopaedic deformities. Two genes causative of Multiple Osteochondromas, Exostosin-1 (EXT1) and Exostosin-2 (EXT2), have been identified, which act as tumour suppressor genes. Osteochondroma can progress towards its malignant counterpart, secondary peripheral chondrosarcoma and therefore adequate follow-up of Multiple Osteochondroma patients is important in order to detect malignant transformation early.This review summarizes the considerable recent basic scientific and clinical understanding resulting in a multi-step genetic model for peripheral cartilaginous tumorigenesis. This enabled us to suggest guidelines for clinical management of Multiple Osteochondroma patients. When a patient is suspected to have Multiple Osteochondroma, the radiologic documentation, histology and patient history have to be carefully reviewed, preferably by experts and if indicated for Multiple Osteochondromas, peripheral blood of the patient can be screened for germline mutations in either EXT1 or EXT2. After the Multiple Osteochondroma diagnosis is established and all tumours are identified, a regular follow-up including plain radiographs and base-line bone scan are recommended.
 ...
PMID:Multiple osteochondromas: clinicopathological and genetic spectrum and suggestions for clinical management. 2023 60

Peripheral chondrosarcoma (PCS) develops as malignant transformation of an osteochondroma, a benign cartilaginous outgrowth at the bone surface. Its invasive, lobular growth despite low-grade histology suggests a loss of chondrocyte polarity. The known genetics of osteochondromagenesis include mosaic loss of EXT1 or EXT2 in both hereditary and non-hereditary cases. The most frequent genetic aberrations in human PCS also include disruptions of CDKN2A or TP53. In order to test the sufficiency of either of these to drive progression of an osteochondroma to PCS, we added conditional loss of Trp53 or Ink4a/Arf in an Ext1-driven mouse model of osteochondromagenesis. Each additional tumour suppressor silencing efficiently drove the development of growths that mimic human PCS. As in humans, lobules developed from both Ext1-null and Ext1-functional clones within osteochondromas. Assessment of their orientation revealed an absence of primary cilia in the majority of mouse PCS chondrocytes, which was corroborated in human PCSs. Loss of primary cilia may be responsible for the lost polarity phenotype ascribed to PCS. Cilia deficiency blocks proliferation in physeal chondrocytes, but cell cycle deregulation is sufficient to rescue chondrocyte proliferation following deciliation. This provides a basis of selective pressure for the frequent cell-cycle regulator silencing observed in peripheral chondrosarcomagenesis. Mosaic loss of Ext1 combined with loss of cell cycle regulators promotes peripheral chondrosarcomagenesis in the mouse and reveals deficient ciliogenesis in both the model and the human disease, explaining biological behaviour including lobular and invasive growth.
 ...
PMID:Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency. 2564 7

Sarcomas represent a complex group of malignant neoplasms of mesenchymal origin and their heterogeneity poses a serious diagnostic and therapeutic challenge. There is therefore a need to elucidate the molecular mechanisms underpinning the pathogenesis of the more than 70 distinguishable sarcoma subtypes. The transcription factor TBX3, a critical developmental regulator, is overexpressed in several cancers of epithelial origin where it contributes to tumorigenesis by different molecular mechanisms. However, the status and role of TBX3 in sarcomas have not been reported. Here we show that a diverse subset of soft tissue and bone sarcoma cell lines and patient-derived sarcoma tissues express high levels of TBX3. We further explore the significance of this overexpression using a small interferring RNA approach and demonstrate that TBX3 promotes the migratory ability of chondrosarcoma, rhabdomyosarcoma and liposarcoma cells but inhibits fibrosarcoma cell migration. This suggested that TBX3 may play a key role in the development of different sarcoma subtypes by functioning as either an oncoprotein or as a brake to prevent tumour progression. To further explore this, TBX3 knockdown and overexpression cell culture models were established using chondrosarcoma and fibrosarcoma cells as representatives of each scenario, and the resulting cells were characterized with regard to key features of tumorigenesis. Results from in vitro and in vivo assays reveal that, while TBX3 promotes substrate-dependent and -independent cell proliferation, migration and tumour formation in chondrosarcoma cells, it discourages fibrosarcoma formation. Our findings provide novel evidence linking TBX3 to cancers of mesenchymal origin. Furthermore, we show that TBX3 may be a biomarker for the diagnosis of histologically dynamic sarcoma subtypes and that it impacts directly on their oncogenic phenotype. Indeed, we reveal that TBX3 may exhibit oncogene or tumour suppressor activity in sarcomas, which suggests that its role in cancer progression may rely on cellular context.
...
PMID:The T-box transcription factor 3 is a promising biomarker and a key regulator of the oncogenic phenotype of a diverse range of sarcoma subtypes. 2690 Sep 51


1 2 Next >>