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

The tumour suppressor gene encoding p53 has been shown from experimental studies to have a crucial role in how cells respond to DNA damage. p53 has important functions in apoptosis, cell-cycle arrest and DNA repair, largely mediated by its activity on gene transcription. However, despite this wealth of in vitro data, its role in how tumours respond to DNA damage induced by chemotherapeutic drugs remains controversial. In this review, we highlight some of the problems surrounding design and analysis of studies of p53 as a prognostic marker of clinical outcome, using ovarian cancer as an example. We aim to build on the knowledge of the published literature in ovarian cancer to identify criteria for clinical studies that should give a more definitive estimate of the role of p53 in clinical drug resistance. A search of three public databases using keywords combined with Boolean operators identified 64 clinical publications investigating the relationship of p53 to clinical outcome following chemotherapy in ovarian cancer. Although 43% of 215 published analyses from the 64 papers reported a significant correlation between p53 status and a clinical endpoint relevant to chemoresistance, only six analyses fulfil minimum criteria and none of these finds a statistically significant correlation of p53 with chemotherapy-resistance endpoints. The results from published clinical studies suggest a more complex role of p53 mutation in the mechanism of resistance in ovarian cancer than is suggested by in vitro studies.
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PMID:Critical evaluation of p53 as a prognostic marker in ovarian cancer. 1514 8

The inhibin field has been perplexed by the information that inhibin alpha is a tumour suppressor in mice yet is elevated in women with ovarian cancer. Furthermore, we have consistently observed a down-regulation or loss of inhibin alpha in prostate cancer patient samples and cell lines. However, our latest data have prompted us to re-evaluate the role of inhibin alpha in prostate and other cancers. Using the analogy of TGF-beta as a springboard for our hypothesis, we offer a unifying model whereby the previously conflicting observations in mice, men and women can be explained. We propose that initially inhibin alpha is tumour-suppressive and is expressed in benign and early-stage primary cancers. Tumour-suppressive inhibin alpha is then silenced as the tumour progresses but is reactivated as a pro-metastatic factor in advanced, aggressive cancers.
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PMID:Cancer progression: is inhibin alpha from Venus or Mars? 1545 Feb 47

In this study, 23 ovarian cancer cell lines were screened using array-comparative genomic hybridization (aCGH) based on large-insert clones at about 1 Mb density from throughout the genome. The most frequent recurrent changes at the level of the chromosome arm were loss of chromosome 4 or 4q, loss of 18q and gain of 20 or 20q; other recurrent changes included losses of 6q, 8p, 9p, 11p, 15q, 16q, 17p, and 22q, and gain of 7q. Losses of 4q and 18q occurred together more often than expected. Evidence was found for two types of ovarian cancer, one typically near-triploid and characterized by a generally higher frequency of chromosomal changes (especially losses of 4p, 4q, 13q, 15q, 16p, 16q, 18p and 18q), and the other typically near-diploid/tetraploid and with fewer changes overall, but with relatively high frequencies of 9p loss, 9q gain, and 20p gain. Multiple novel changes (amplifications, homozygous deletions, discrete regions of gain or loss, small overlapping regions of change and frequently changed clones) were also detected, each of which might indicate the locations of oncogenes or tumour suppressor loci. For example, at least two regions of amplification on chromosome 11q13, one including cyclin D1 and the other the candidate oncogene PAK1, were found. Amplification on 11q22 near the progesterone receptor gene and a cluster of matrix metalloproteinase loci was also detected. Other potential oncogenes, which mapped to regions found by this study, included cyclin E and PIK3C2G. Candidate tumour suppressor genes in regions of loss included CDKN2C, SMAD4-interacting protein and RASSF2.
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PMID:Analysis of ovarian cancer cell lines using array-based comparative genomic hybridization. 1558 66

WWOX is a candidate tumour suppressor gene that exhibits LOH or homozygous deletion in several tumour types. As well as the predominant full-length transcript (variant 1) there also exist alternatively spliced transcripts found previously only in malignant tissue. It has been suggested that proteins encoded by these variants may interfere with normal WWOX function in a dominant negative fashion. The most prevalent alternate transcript demonstrated in ovarian cancer is variant 4, which lacks exons 6-8. Here, we report the first comparison of the mRNA expression of WWOX variants 1 and 4 in human ovarian tumours and normal ovaries, and correlate expression with clinical data. We demonstrate significantly lower WWOX variant 1 expression in tumours than in normal ovaries. This reduction was not associated with any specific clinical subgroup. Variant 4 was expressed at low levels, and significantly associated with high grade and advanced stage ovarian cancer. Furthermore, tumours co-expressing variant 4 and relatively high levels of variant 1 showed significantly worse survival than tumours expressing variant 1 alone. However, variant 4 was also frequently identified in non-malignant ovarian tissue. These results support the role of WWOX variant 1 as a suppressor of ovarian tumourigenesis, but the role of variant 4 remains speculative.
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PMID:WWOX mRNA expression profile in epithelial ovarian cancer supports the role of WWOX variant 1 as a tumour suppressor, although the role of variant 4 remains unclear. 1587 Aug 86

LZTS1 has been shown to have tumour suppressor activities against prostate and breast cancer and is located within a region of frequent loss of heterozygosity (LOH) at 8p22 in ovarian cancer. We have analysed the expression of LZTS1 in ovarian cancer and found no evidence of loss of expression relative to normal ovarian surface epithelial cells. We have also analysed the coding region of the LZTS1 gene in 87 primary ovarian adenocarcinomas by DHPLC and detected a single silent somatic mutation. These data indicate that LZTS1 is not the target of LOH at 8p22 in ovarian cancer.
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PMID:Mutation and expression analysis of LZTS1 in ovarian cancer. 1587 81

Although population-based studies have unequivocally reported an increased risk of ovarian cancer in women with endometriosis, the biological evidence supporting the idea of endometriosis as a preneoplastic condition is scanty and not well substantiated. The fundamental features of human neoplasms (monoclonal growth, genetic changes, mutations in tumour suppressor genes and replicative advantage) have been evaluated in endometriotic lesions but results obtained are discordant. It is plausible that ectopic glands may expand monoclonally but the entity of this phenomenon is debated. According to some allelotyping studies, from one-third to one-half of endometriosis lesions would harbour somatic genetic changes in chromosomal regions supposed to contain genes involved in ovarian tumourigenesis, especially for the endometrioid histotype. These findings would be consistent with the progression model for carcinogenesis from the benign precursor to ovarian cancer but they could not be unequivocally replicated. Gene mutational studies are rare in this context. A single group has found missense mutations and deletions of PTEN gene in about 20% of ovarian endometriotic cysts. Moreover, in a model of genetically engineered mice harbouring an oncogenic allele of K-ras resulting in benign lesions reminiscent of endometriosis, a conditional deletion of PTEN caused the progression towards the endometrioid tumour. Based on these data, the causal link between endometriosis and ovarian endometrioid/clear cell carcinomas remains to be defined both in terms of entity of association and of underlying molecular mechanisms.
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PMID:Molecular mechanisms and biological plausibility underlying the malignant transformation of endometriosis: a critical analysis. 1617 12

We had previously defined by allele loss studies a minimal region at 6q27 (between D6S264 and D6S297) to contain a putative tumour suppressor gene. The p90 ribosomal S6 kinase-3 gene (p90 Rsk-3, RPS6KA2) maps in this interval. It is a serine-threonine kinase that signals downstream of the mitogen-activated protein kinase pathway. It is expressed in normal ovarian epithelium, whereas reduced or absent in tumours or cell lines. We show that RPS6KA2 is monoallelically expressed in the ovary suggesting that loss of a single expressed allele is sufficient to cause complete loss of expression in cancer cells. Further, we have identified two new isoforms of RPS6KA2 with an alternative start codon. Homozygous deletions were identified within the RPS6KA2 gene in two cell lines. Re-expression of RPS6KA2 in ovarian cancer cell lines suppressed colony formation. In UCI101 cells, the expression of RPS6KA2 reduced proliferation, caused G1 arrest, increased apoptosis, reduced levels of phosphorylated extracellular signal-regulated kinase and altered other cell cycle proteins. In contrast, small interfering RNA against RPS6KA2 showed the opposite effect in 41M cells. The above results suggest that RPS6KA2 is a putative tumour suppressor gene to explain allele loss at 6q27.
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PMID:RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer. 1687 54

Ubiquitylation is an important regulatory mechanism of many cellular processes. The breast and ovarian cancer-specific tumour suppressor BRCA1 is well acknowledged to be a RING/E3 ubiquitin ligase, however, identification of its physiological substrates has proved elusive. Recently published data have shown that the BRCA1-interacting protein CtIP is in fact ubiquitylated by BRCA1, and opens new avenues for the isolation of other substrate proteins.
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PMID:BRCA1 ubiquitylation of CtIP: Just the tIP of the iceberg? 1702 45

Syringolin A is a new plant elicitor produced by the plant pathogen Pseudomonas syringae pv. syringae. The goal of this study was to investigate whether syringolin A exhibits anti-proliferative properties in cancer cells. The treatment of human neuroblastoma (NB) cells (SK-N-SH and LAN-1) and human ovarian cancer cells (SKOV3) with syringolin A (0-100 microm) inhibited cell proliferation in a dose-dependent manner. The IC(50) (50% inhibition) for each cell line ranged between 20 microm and 25 microm. In SK-N-SH cells, the treatment with 20 microm syringolin A led to a rapid (24 h) increase of the apoptosis-associated tumour suppressor protein p53. In addition, we found that the treatment of SK-N-SH cells caused severe morphological changes after 48 h such as rounding of cells and loss of adherence, both conditions observed during apoptosis. The induction of apoptosis by syringolin A was confirmed by both poly (ADP-ribose) polymerase (PARP) cleavage and annexin V assay. Taken together, we show for the first time that the natural product syringolin A exhibits anti-proliferative activity and induces apoptosis. Syringolin A and structurally modified syringolin A derivatives may serve as new lead compounds for the development of novel anticancer drugs.
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PMID:Syringolin A, a new plant elicitor from the phytopathogenic bacterium Pseudomonas syringae pv. syringae, inhibits the proliferation of neuroblastoma and ovarian cancer cells and induces apoptosis. 1710 42

Beclin 1 is is an autophagy gene, the role of which as a tumour suppressor has recently been recognized in a few studies. We examined the expression of Beclin 1 protein in 212 primary human brain tumours, including 97 high-grade glial tumours, 29 low-grade glial tumours, 4 grade III meningiomas, 19 grade II meningiomas, 52 grade I meningiomas, and 11 medulloblastomas. In 94 cases, including 56 glial tumours, 35 meningiomas, and 3 medulloblastomas we also assessed Beclin 1 mRNA expression by real-time RT-PCR. In most high-grade astrocytic, ependymal neoplasms and atypical meningiomas we found a decrease of cytoplasmic protein expression that was, instead, high in the majority of low-grade tumours and in medulloblastomas. The expression level of Beclin 1 mRNA was significantly lower in glioblastomas than in grade II (p=0.04) and grade I (p=0.01) astrocytomas; in grade III than in grade I astrocytomas (p=0.01); in grade II than in grade I meningiomas (p=0.03); and in all glial tumours when compared to all meningiomas (p<0.0001). Cytoplasmic expression is thought to be linked to the functional protein. Our observations are in line with studies that demonstrated decreased expression of Beclin 1 in human breast, ovarian, prostate and ovarian cancer and furtherly support its involvement also in brain tumours, which had previously been demonstrated in a few experimental studies, both in spontaneous and in therapy-induced autophagy. Furthermore, our study suggests possible differences of Beclin 1 involvement and its role among the different histotypes of brain neoplasms. Further studies are needed to highlight Beclin 1 function in tumour suppression and/or in tumour survival through autophagy and other related programmed cell death processes in brain tumours.
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PMID:Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours. 1720 25


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