Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gelatinase A transcriptional regulation is the consequence of combinatorial interactions with key promoter and enhancer elements identified within this gene. A potent 40 bp enhancer response element, RE-1, located in the near 5' flanking regions of the rat and human gelatinase A genes drives high-level expression in glomerular mesangial cells (MCs). Southwestern-blot analysis of MC nuclear extracts revealed specific interactions of RE-1 with at least four proteins, of which three have been identified as p53, activator protein 2 and the single-stranded DNA-binding factor Y-box protein-1 (YB-1). In the present study, we report the identification of a fourth 17 kDa RE-1-binding protein as the rat homologue (nm23-beta) of the human nm23-H1 metastasis suppressor gene. Recombinant nm23-beta protein bound only the single-stranded forms of the RE-1 sequence. Mutagenesis revealed direct interaction of nm23-beta with a repeat sequence, 5'-GGGTTT-3', shown previously to specifically interact with YB-1 [Mertens, Harendza, Pollock and Lovett (1997) J. Biol. Chem. 272, 22905-22912], and recombinant nm23-beta protein competed for single-stranded YB-1 binding. Transient transfection of MC with an nm23-beta expression plasmid within the context of a RE-1/simian virus 40 promoter/luciferase reporter yielded a concentration-dependent repression (80-90%) of luciferase activity in MC and Rat1 fibroblasts. A similar pattern of nm23-beta repression was demonstrated within the context of the RE-1/homologous gelatinase A promoter. Co-transfection of nm23-beta blocked YB-1-mediated activation of transcription and expression of gelatinase A. Nm23-beta may be an important physiological regulator of gelatinase A transcription that acts by competitive interference with the single-stranded transactivator YB-1. Gelatinase A is a key mediator of tumour metastasis, suggesting that competitive suppression of transcription by nm23-beta (or the human nm23-H1) may be a component of the reduced metastatic capabilities of cells expressing high levels of this protein.
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PMID:Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). 1201 Jan 25

The transmembrane 4 superfamily member KAI1/CD82, a metastasis suppressor, is correlated inversely with the progression and invasion of several tumors. It is capable of inhibiting metastasis without affecting tumorigenicity per se. KAI1/CD82 expression is down-regulated in the progression of common solid epithelial tumors of adulthood. Mutation of p53 is suggested to be involved in the modulation of KAI1. As little is known about its expression and possible prognostic impact in pediatric tumors, we investigated KAI1/CD82 expression in cell lines and primary tumor samples from pediatric tumors of neuroectodermal origin, neuroblastoma and Ewing's sarcoma family tumor. Twenty-four of 29 Ewing's sarcoma family tumor cell lines, independent of p53 status, showed KAI1 mRNA positivity by reverse transcription-PCR analysis in contrast to zero of eight neuroblastoma cell lines. Among 13 primary Ewing's sarcoma family tumor samples from patients with different disease extension, KAI1 mRNA expression was low as detected by reverse transcription-PCR. Twenty of 30 primary neuroblastoma specimens were KAI1-negative by immunofluorescence analysis whereas the remaining 10 gave weak to moderate staining patterns. There was no apparent correlation of KAI1 expression with any clinical or genetic features of the patients whose tumor samples were studied. Consequently, KAI1 may not be of prognostic relevance in this group of tumors although there may be some role for KAI1 modulation in the biology of these neuroectodermal tumors.
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PMID:Frequent low level expression in Ewing sarcoma family tumors and widespread absence of the metastasis suppressor KAI1/CD82 in neuroblastoma. 1214 7

The molecular basis for the loss of KAI1 expression in invasive and metastatic tumors and tumor cell lines is not understood. Recently, identification of a sequence with homology to the consensus p53-binding motif in the promoter of the KAI1 metastasis suppressor gene, has led to a proposal that transcriptional regulation by p53 controls expression of KAI1, and that a dramatic down-regulation of KAI1 mRNA levels in invasive tumors and many tumor cell lines, is directly due to loss of p53 function. We have tested this hypothesis by assessing KAI1 mRNA levels in a series of 22 cell lines derived from bladder and prostate cancers, in which we confirmed the p53 gene sequence and characterized the functional status of the endogenous p53 protein. We anticipated that cell lines expressing p53 capable of transactivation should express high levels of KAI1 mRNA compared with cell lines expressing defective p53, or which were p53-null. KAI1 mRNA levels were determined by northern analysis using a full-length KAI1 cDNA probe, and varied widely between cell lines examined. However, there was no association between these levels and p53 status. Furthermore, transfection of representative cell lines with wild-type p53, or exposure to DNA damaging agents, had no effect on KAI1 mRNA levels. Our data suggest that p53 is not a major factor regulating levels of KAI1 mRNA in bladder and prostate cancer cell lines.
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PMID:Relationship between expression of KAI1 metastasis suppressor gene, mRNA levels and p53 in human bladder and prostate cancer cell lines. 1247 42

To investigate the genetic mechanism of metastatic spread in hepatocellular carcinoma (HCC), we analyzed genomic changes in lung or liver metastases and the corresponding primary tumors (83 tumor samples) in 18 patients who underwent orthotopic liver transplantation. We studied the incidence of microsatellite instability (MSI) and loss of heterozygosity (LOH) involving 8 highly polymorphic microsatellite markers and the polyA tract, Bat26. We also sought alterations of p53 and beta-catenin gene mutations. High MSI (>30-40% of the loci analyzed) was found only in primary tumors (11%), whereas LOH was observed in 50% of primary and in 39% of recurrent tumors. p53 mutations were found in 2 cases of primary HCC but not in the corresponding metastases. P53 was overexpressed in 4 primary HCC (22%) and 7 metastases (39%). The percentage of beta-catenin gene mutations was low (6%). Lung metastases retained the D16S402 microsatellite abnormalities observed in the primary tumors, whereas recurrent liver tumor did not (p = 0.02). In conclusion, LOH and P53 protein overexpression, rather than mutations in the p53 or beta-catenin genes or MSI, seem to be involved in the spreading of HCC, suggesting the presence of metastasis suppressor genes in the vicinity of the chromosomal loci in question.
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PMID:Analysis of chromosomal instability in pulmonary or liver metastases and matched primary hepatocellular carcinoma after orthotopic liver transplantation. 1264 Jun 82

Drg-1 was previously identified (N. van Belzen et al., Lab. Investig., 77: 85-92, 1997) as a gene that was up-regulated by the induction of differentiation in a colon carcinoma cell line in vitro. Subsequently, this gene was found to be regulated by several factors including hypoxia, androgen, p53, and N-myc. Recently, Drg-1 has also been shown to be involved in tumor progression in animals, although the clinical significance of its involvement remains to be investigated. To clarify the functional role of Drg-1 in prostate cancer, we examined a clinical archive of cancer specimens for the expression of Drg-1 by immunohistochemistry. We found that the expression of Drg-1 had a significant inverse correlation with the Gleason grading and the overall survival rate of patients. In particular, the gene expression in patients with lymph node or bone metastasis was significantly reduced as compared with those with localized prostate cancer, suggesting that the function of Drg-1 is negatively involved in metastatic progression of the disease. To further clarify the function of this gene in the advancement of prostate cancer, a spontaneous metastasis assay was performed in a severe combined immunodeficient (SCID) mouse model. We found that Drg-1 almost completely inhibited lung colonization of highly metastatic prostate cancer cells without affecting the growth of the primary tumors. These results strongly suggest that Drg-1 is a candidate metastasis suppressor gene for prostate cancer and may serve as a useful prognostic marker.
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PMID:The Drg-1 gene suppresses tumor metastasis in prostate cancer. 1270 52

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. Thus, in order to understand the process of acquisition of metastatic phenotypes in cancer cells, it is indispensable to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells. For this reason, we have been searching for genes that are preferentially altered in metastatic lung cancer cells and have activities to regulate their metastatic potentials. In lung cancer, both the p16INK4A/RB and p53 genes are frequently inactivated and are critical determinants for the regulation of cell growth and apoptosis. However, it still remains unclear whether these genes are also involved in the regulation of metastatic potential in lung cancer cells. Recently, we identified a novel myosin family gene, MYO18B, from the chromosome 22q12.1 region which shows frequent loss of heterozygosity in advanced lung cancer, and we found that this gene is inactivated in approximately 50% of lung cancers by deletions, mutations and methylation. Furthermore, restoration of MYO18B expression suppressed anchorage-independent growth of lung cancer cells. Thus, it was indicated that the MYO18B gene is a strong candidate for a metastasis suppressor gene of human lung cancer. Further functional and biological studies of the MYO18B gene will help us understand the molecular pathway of human lung cancer progression.
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PMID:Genetic alterations responsible for metastatic phenotypes of lung cancer cells. 1274 77

Recent data have proposed that transcription of the KAI1 metastasis suppressor gene is directly mediated by p53 and that loss of KAI1 expression in advanced prostate cancer is simply due to loss of p53 function after mutation. To investigate this possibility, we have examined KAI1 mRNA (by in situ hybridisation) and p53 protein expression (by immunohistochemistry) as an indicator of wildtype or mutant p53, in a series of 77 paraffin-embedded prostate tissue samples, including post-mortem normal prostates (2), benign prostatic hyperplasia (10), localised cancer (grades 4-6, 25; grades 7-9, 21) and prostate-derived bony metastases (19). Overall, we confirmed that expression of KAI1 mRNA decreased from normal tissue, through localised cancer to bony metastases (P=0.055, tending to significance), while levels of p53 staining significantly increased with cancer progression (P=0.046). These were consistent with the possibility that loss of p53 function might be responsible for loss of KAI1 mRNA. However, by close examination of KAI1 and p53 in adjacent tissue sections, we found no correlation between decreased levels of KAI1 mRNA and overexpression of p53 protein (P=0.497). In addition, high levels of KAI1 mRNA could be identified in samples irrespective of p53 staining. Our data suggest that mutation of p53 is independent of the loss of KAI1 mRNA, and do not support a role for p53 in regulating the expression of KAI1.
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PMID:Downregulation of KAI1 mRNA in localised prostate cancer and its bony metastases does not correlate with p53 overexpression. 1280 79

MKK4, located in close proximity to p53 gene, is thought to be a tumor suppressor and a metastasis suppressor gene. A low-rate MKK4 gene alteration has been found in a few tumor types, including breast and pancreatic. A suppressor activity for prostate and ovarian tumor metastasis has also been suggested. To understand the pathobiologic roles of MKK4 in tumorigenesis, we examined the phenotypic changes in response to perturbation of the MKK4 expression in breast and pancreatic cancer cell lines. Ectopic expression of MKK4 by adenoviral delivery in MKK4-negative cancer lines stimulated the cell proliferation and invasion, whereas knockdown of MKK4 expression by small interference RNA in an MKK4-positive breast cancer cell line, MDA-MB-231, resulted in decreased anchorage-independent growth, suppressed tumor growth in mouse xenograft model, and increased cell susceptibility to apoptosis brought by stress signals such as serum deprivation. These results argue that MKK4 functions as a pro-oncogenic molecule instead of a suppressor in breast and pancreatic tumors.
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PMID:Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. 1518 66

Oral Squamous Cell Carcinoma (OSCC) is a common malignancy. Treatment failure is mainly due to loco-regional disease recurrence. KAI1 is a newly discovered metastasis suppressor gene. Fifty-seven patients with primary OSCC underwent surgery alone or surgery and adjuvant radiotherapy. Immunohistochemical evaluation of KAI1/CD82 and p53 proteins was carried out on specimen obtained at surgery. Within neoplastic fields, KAI1/CD82 expression was downregulated and negative in 42/57 (73.7%) cases. p53 expression was positive in 26/57 (45.6%) cases. No correlation was noted between KAI1/CD82 and p53 expression or clinicopathological parameters. Univariate and multivariate Cox proportional hazard models showed a correlation between KAI1/CD82 expression with disease free survival (P = 0.01, P = 0.009) and overall survival (P = 0.04, P = 0.053) respectively.
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PMID:Down-regulation of KAI1/CD82 protein expression in oral cancer correlates with reduced disease free survival and overall patient survival. 1531 88

It has been proposed that a 356 amino acid protein encoded by the MIM (Missing In Metastasis) gene on Chromosome 8q24.1, is a bladder cancer metastasis suppressor. Recently, Machesky and colleagues [Biochem. J. 371 (2003) 463] identified MIM-B, a 759 amino acid protein, of which the C-terminal 356 amino acids are almost identical to MIM. Importantly, PCR primers and Northern Blotting probes used in the studies of MIM in bladder cancer did not distinguish between sequences specific for MIM or MIM-B, thus the importance of either protein to bladder cancer remains unclear. We have used primer sequences specific for either MIM or MIM-B to explore the possible functional significance of MIM and MIM-B to bladder cancer cell behaviour. We have compared MIM and MIM-B mRNA levels in a non-tumourigenic, non-invasive, transformed uro-epithelial cell line versus 15 bladder cancer cell lines of differing in vitro invasive abilities, as well as in five cell lines clonally isolated from the BL17/2 bladder tumour cell line, whose in vitro and in vivo invasive abilities have been determined. MIM and MIM-B mRNA levels varied widely between cell lines. Down-regulation of MIM and MIM-B occurred in 6/15 (40%) lines but lines showing down-regulation differed between MIM and MIM-B. Reduced levels of MIM and MIM-B in BL17/2 were further reduced in 2/5 (40%) sublines (MIM and MIM-B). Importantly, there was no association between MIM or MIM-B expression and invasive behaviour in vivo or in vitro. Treatment of representative cell lines with 5-aza-2-deoxycytidine failed to induce MIM or MIM-B expression. Furthermore, there was no association between MIM or MIM-B mRNA levels and p53 functional status. Our data indicate that down-regulation of MIM and/or MIM-B expression can occur in bladder cancer cell lines but is not associated with increased invasive behaviour. Our data also suggest that in those cell lines with reduced levels of MIM and MIM-B mRNA, down-regulation is unlikely to be due to promoter hypermethylation or loss of p53 function.
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PMID:Expression and regulation of MIM (Missing In Metastasis), a novel putative metastasis suppressor gene, and MIM-B, in bladder cancer cell lines. 1548 40


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