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)

Genetic and molecular analyses of Drosophila have shown that tumorigenesis may arise from inactivation of single genes controlling cell growth and differentiation. Recessive mutations in a series of genes interrupt the differentiation of primordial cells and result in overgrowth, producing either hyperplasia or neoplasia. In mutant animals tumours form in either the optic centres of the larval brain, the imaginal discs or the haemopoietic organs. In Drosophila 17 genetic loci giving rise to neoplasia and six loci producing hyperplasia have been identified. The lethal(2)giant larvae gene constitutes the prototype of these genes. Its molecular cloning and analysis have demonstrated that the tumor phenotype results from a lack of gene function. Furthermore, tumour prevention was achieved by introducing a normal copy of l(2)gl into the genome of l(2)gl- deficient animals, showing that the l(2)gl gene behaves as a tumour suppressor or anti-oncogene. Melanomas of genetic origin develop in interspecies hybrids of the fish Xiphophorus. The melanoma appears when a sex linked chromosomal gene (Tu) is present among the progeny animals lacking an autosomal locus Differentiation, which acts as a tumour suppressor gene. A sequence homologous to the erb-B gene can be associated to the sex chromosomal Tu locus. This gene encodes a receptor tyrosine kinase related to the EGF-receptor, and its activation and overexpression are thought to play a critical part in melanoma formation.
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PMID:The fruit fly Drosophila and the fish Xiphophorus as model systems for cancer studies. 210 23

Wilms' tumour is an embryonic kidney tumour thought to arise through aberrant mesenchymal stem cell differentiation and to result from loss of function of a 'tumour suppressor' gene(s). Both sporadic and syndrome-associated Wilms' tumours are accompanied by an increased frequency of abnormalities of the urinary tract and genitalia. Deletional analysis of individuals with the WAGR syndrome (for, Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) showed that a Wilms' tumour gene lies at chromosomal position 11p13. This led to the isolation of a candidate Wilms' tumour gene, encoding a zinc-finger protein which is likely to be a transcription factor. To gain insight into the role of this candidate gene in normal development and tumorigenesis, we have now performed in situ messenger RNA hybridization on sections of human embryos and Wilms' tumours. The candidate Wilms' tumour gene is expressed specifically in the condensed mesenchyme, renal vesicle and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli and in cells approximating these structures in tumours. The other main sites of expression are the genital ridge, fetal gonad and mesothelium. These data suggest that (1) this candidate is indeed a Wilms' tumour gene, (2) the associated genital abnormalities are pleiotropic effects of mutation in the Wilms' tumour gene itself, in support of recent genetic analysis, and (3) this gene has a specific role in kidney development and a wider role in mesenchymal-epithelial transitions.
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PMID:The candidate Wilms' tumour gene is involved in genitourinary development. 216 59

Genetic tumours of Xiphophorus are one of the classical experimental models that underline the concept that cancers develop as a result of abnormal gene expression. Formal genetics has indicated that cancer development in Xiphophorus starts when oncogenes are expressed abnormally due to elimination of tumour suppressor genes. The suppressor gene Diff seems to suppress malignancy by controlling terminal differentiation of cells. It appears now that control of terminal differentiation may also be one of the properties of human tumour suppressor loci, in particular the Rb gene. Although it is difficult at this point to envision which molecular or biochemical function of tumour suppressor genes we might be able to identify, research on tumour suppression will at least allow another glimpse at how basic mechanisms of cell differentiation and multiplication operate. It is not clear, however, if elimination of tumour suppressor genes alone is sufficient to elicit the fully malignant phenotype. Cytogenetic studies have shown various nonrandom chromosomal abnormalities in those human tumours in which elimination of a tumour suppressor gene seems to be a critical step in tumorigenesis. In Xiphophorus, it is obvious from our molecular studies that additional genetic events can contribute to the malignant phenotype. Of these, amplification of cellular DNA may have a role in malignant progression of melanomas. At this point, the exact contribution of amplification to genetic melanoma is unclear. Judging from the role of amplification in human and murine tumours, the significance of amplification, in addition to suppressor elimination, in melanomas of Xiphophorus is likely to be high.
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PMID:Genetic suppression of malignancy. 268 Sep 48

Colorectal tumorigenesis evolves through a series of molecular genetic changes, providing putative markers for tumour progression. This study investigated the relation between expression of the tumour suppressor gene p53 and splice variants v5 and v6 of the cell adhesion molecule CD44 by immunohistochemistry on tissue samples of early adenomas (n = 12), late adneomas (n = 12), Dukes's A and B carcinomas (n = 21), and Dukes's C and D carcinomas (n = 22) and compared these results with expression of these proteins in normal colonic mucosa (n = 17). A statistically significant trend of increasing expression was seen for both p53 (p < 0.005) and CD44 variant exon v6 (p < 0.0005) in subsequent stages of this tumour progression model. High expression of CD44 v5 was seen in most colorectal neoplasms (83%-96%), independent of stage. A statistically significant correlation was present between p53 expression and expression of variant v6 of CD44 (p < 0.01). Both p53 expression and CD44 v6 expression in adenomas increased with the degree of dysplasia (p < 0.05). The results of this study show that mutant p53 protein and variant v6 of the CD44 glycoprotein are markers of tumour progression in colorectal cancer.
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PMID:Expression of mutant p53 protein and CD44 variant proteins in colorectal tumorigenesis. 754 Oct 11

Overexpression of the p53 tumour suppressor gene is one of the most common abnormalities in primary human cancers and appears to be a result of point mutation within a highly conserved region of the gene with subsequent encoding for a mutant, more stable protein. In the study, 71 surgically resected hepatocellular carcinomas (HCC) were examined to study the expression of the p53 gene, its relation with clinicopathological parameters and its prognostic significance. Using immunohistochemical detection for mutant p53 protein with monoclonal antibody PAb1801, p53 overexpression was found in 22 tumours (31%) but in none of the non-tumorous liver specimens. Overexpression of p53 was more frequent in tumours with poor cellular differentiation (P = 0.01), in tumours > 5 cm in diameter (P = 0.05), and in those with giant cells present (P = 0.03) and, less significantly, of massive type of Eggel's classification (P = 0.06). It did not have any significant correlation with hepatitis B or C status, background liver disease or serum alpha-fetoprotein levels, nor was it related to tumour invasiveness (venous permeation, direct liver invasion and tumour microsatellite formation). In addition, the presence of p53 mutant protein did not influence tumour recurrence or patients' survival rates. The data suggested that p53 mutation in HCC was associated with a later stage of oncogenesis. However, it was not apparently related to tumour invasiveness/aggressiveness and prognosis.
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PMID:Overexpression of p53 in hepatocellular carcinomas: a clinicopathological and prognostic correlation. 754 99

Loss of function of one or both of the two tumour suppressor genes p53 and RB-1 has been recognised as an important step in the development of a variety of human neoplasias for some time. By virtue of the ability to manipulate the genome of murine embryonic stem cells in culture, it has become possible to generate strains of mice which bear inactivations of the murine counterparts of these genes. This article attempts to bring together some of the many results obtained from these murine strains which are shedding light both on the normal role played by both of these genes and the consequences of their dysfunction. Surprisingly neither gene product is revealed to have an indispensable role at the level of the single cell. Hence, even though the Rb-1 gene product clearly has an important role in cell cycle regulation animals constitutively deficient in this gene develop relatively normally for the first 10 days of embryogenesis. It is only at and beyond this stage of development that a requirement for Rb-1 becomes clear, in the regulation of certain cell populations through control of both proliferation and apoptosis. That loss of function of Rb-1 is associated with tumorigenesis is confirmed by the development of tumours of the pituitary gland within heterozygotes. The retinas of these animals, the target organ for tumorigenesis in human RB-1 heterozygotes, remain unaffected. The majority of mice homozygous for an inactivating p53 mutation survive to birth, but then rapidly succumb to tumorigenesis. Heterozygotes also develop tumours, but with a delayed time course and altered spectrum. Analysis of several tissue types from the mutant animals has shown p53 to be crucial for the normal induction of apoptosis following DNA damage, and it is thought that failure of this process is a key predisposing step towards tumorigenesis within the mutant animals. Finally, studies on these and other transgenic strains have revealed interactions between pathways governed by these two genes. For example, the fate of Rb-1 deficient cells has been shown, in some tissues at least, to be dependent upon the functional status of p53.
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PMID:Murine models of neoplasia: functional analysis of the tumour suppressor genes Rb-1 and p53. 755 30

The Deleted in Colorectal Cancer (DCC) gene is a candidate tumour suppressor gene encoding a neural cell adhesion molecule-like transmembrane protein. Over the last year, data supporting DCC inactivation in multiple tumour types have continued to accumulate. Functional studies suggest that DCC may participate in signalling pathways that regulate cell proliferation and/or differentiation, two cellular processes that often go awry during tumorigenesis.
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PMID:DCC: linking tumour suppressor genes and altered cell surface interactions in cancer? 757 91

Human pituitary tumours account for 10% of intracranial neoplasms. These tumours are usually sporadic and benign; malignant change and metastasis are extremely rare events. Autosomal dominant inheritance of MEN 1 accounts for a minority of pituitary tumours. Pituitary tumours have been found to be monoclonal in several studies. This would suggest that an intrinsic genetic pituitary defect is pivotal in the pathogenesis of these tumours. However, this concept does not exclude a role for the hypothalamus in the genesis of pituitary tumours; the trophic function of several hypothalamic peptides could promote initiation of the genetic event or facilitate a sequence of events leading to clonal expansion of the transformed cell. There has been modest progress made in the elucidation of the intrinsic genetic pituitary cell abnormalities that underlie pituitary tumorigenesis. A mutant alpha subunit of the Gs gene, designated gsp, which results in constitutive activation of adenylyl cylcase has been described in a subset of GH cell adenomas. Loss of genetic material on chromosome 11q13, the locus of the MEN 1 gene, is found in under 20% of pituitary adenomas, suggesting that inactivation of a tumour suppressor gene at this locus may be significant in the tumorigenic process. H-ras point mutations have been described in distant metastatic pituitary tumour secondaries. The genetic abnormalities described occur in only a small subset of pituitary tumours, indicating that the more significant tumour promoting genes are still to be discovered.
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PMID:Molecular pathogenesis of pituitary tumours. 762 83

The connections between cancer and the basic machinery of the cell cycle have taken a surprisingly long time to become apparent. However, the past 2 years has seen a dramatic increase in the number of cell cycles regulators that have been implicated as either protooncogenes or as tumour suppressor genes. In this review I will attempt to show how perturbations in the known cell cycle regulators may play a part in the process of oncogenesis.
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PMID:Cyclins, CDKs and cancer. 764 8

We describe the pathology of a cohort of 80 mice heterozygous for an inactive allele of the Rb-1 tumour suppressor gene. The majority of these mice developed locally invasive tumours, arising from the pituitary gland. The time of onset of overt signs of disease in mice known to have inherited their mutant allele paternally shows a small but statistically significant shift to the lower end of the spectrum, suggesting that tumorigenesis is influenced by gametic imprinting. In situ hybridisation analysis demonstrates the presence in the tumours of pro-opiomelanocortin mRNA, which is normally found both in corticotroph and melanotroph cells. Mice within this cohort also develop systemic defects. Most notably, there is increased siderosis in the spleen indicating the possibility of an abnormality in red blood cell turnover. This is consistent with the abnormalities of erythropoiesis described previously in homozygous Rb-1-deficient mice. In addition, a proportion of mice developed liver steatosis, probably representing the end organ effects of hormonal imbalance as a direct consequence of tumour presence. A significant proportion showed C cell hyperplasia in the thyroid. The spectrum of pathology in mice differs from that in the human but does provide a useful model of site-specific tumour predisposition.
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PMID:Effects of heterozygosity for the Rb-1t19neo allele in the mouse. 773 16


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