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)

The p53 gene is believed to be mutated or deficient in over 50% of human tumours, and is therefore considered to be instrumental in the process of carcinogenesis. Recently in humans, homologues of p53 (such as p73 and p63) have been isolated. In our studies in fish, we have been isolating tumour suppressor genes with a view to their potential use to study genotoxins in the aquatic environment. In this paper, we report the characterisation of the first non-mammalian p73 cDNA, isolated from barbel (Barbus barbus), a freshwater cyprinid fish indigenous to UK rivers. The deduced barbel p73 amino acid sequence has a high homology with human p73 alpha: the proteins are 641 and 636 aa in length, respectively, and there is a 72% identity over the entire sequence length of the protein (over 90% in the putative DNA binding domain). The level of conservancy for p73 is considerably higher across class (from man to fish), than for p53 and it may therefore have particular value in studies on environmental mutagenesis. Northern analysis showed expression of three p73 mRNA transcripts/homologues. The patterns of p73 tissue expression in the barbel differed from the expression of p53 mRNA, suggesting specific functional roles for the two genes.
Comp Biochem Physiol B Biochem Mol Biol 2000 May
PMID:Molecular characterization of the first non-mammalian p73 cDNA. 1082 64

The hdm2 protein negatively regulates p53 tumour suppressor activity. Upon binding to p53, hdm2 stimulates p53 degradation and inhibits its transcriptional activity. Moreover, the hdm2 protein is overexpressed in various tumours inactivating p53. We report here that an octamer synthetic peptide derived from p53 inhibits the p53-hdm2 interaction in vitro. In cellular assays, this untagged peptide penetrates tumour cells and induces the accumulation of p53. The accumulation of p53 leads to its activation. Two gene products transcriptionally regulated by p53, p21Waf1/Cip1 and hdm2, are induced in the presence of the peptide. When used with tumour cells that overexpress hdm2, the peptide induces the death of these tumour cells by apoptosis. The mode of action of this peptide differs from that of DNA-damaging agents (e.g. cisplatin) in that it does not induce p53 phosphorylation on serine 15. This work validates with a low molecular mass molecule our current knowledge on the regulation of the p53 pathway by the hdm2 protein. It also shows that inhibitors of the p53-hdm2 interaction are very attractive candidates for the activation of the p53 pathway in tumours expressing wild-type p53.
J Mol Biol 2000 May 26
PMID:A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. 1086 Jul 36

The tumour suppressor gene PTEN, localized to 10q23.3, is the susceptibility gene for Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba (BRR) syndrome, two hamartoma syndromes with an increased risk of breast and thyroid tumours. Somatic mutations have been found in a variety of human tumours. Functional studies have revealed that PTEN plays a fundamental role in cellular growth, death, adhesion and migration. RNA in situ hybridization using the pten coding region in mouse embryos showed ubiquitous transcription, providing evidence that pten could play a versatile role throughout murine development. Nothing is known regarding the pattern of PTEN expression during human development. Here, we present the pattern of PTEN expression during human development using a specific monoclonal antibody and examine the relationship of the temporal and spatial expression pattern to the clinical manifestations of CS and BRR, the somatic genetic data in sporadic cancers, the murine knockout models and the RNA expression data in mouse embryos. We observed mainly high-level PTEN expression in tissues (e.g. skin, thyroid and central nervous system) known to be involved in CS and BRR. In addition, we identified tissues (e.g. peripheral nervous system, autonomomic nervous system and upper gastrointestinal tract) with high PTEN expression not commonly known to play a role in these syndromes nor in sporadic tumorigenesis in those organs. This knowledge may help in identifying roles for PTEN which, as of today, are unknown or even unsuspected.
Hum Mol Genet 2000 Jul 01
PMID:Expression of the PTEN tumour suppressor protein during human development. 1086 Dec 90

Radiation injury to cells enhances C-terminal phosphorylation of p53 at both Ser315 and Ser392 in vivo, suggesting the existence of two cooperating DNA damage-responsive pathways that play a role in stimulating p53-dependent gene expression. Our previous data has shown that cyclin A-cdk2 is the major enzyme responsible for modifying p53 at Ser315 in vivo after irradiation damage and in this report we dissect the mechanism of cyclinA-cdk2 binding to and phosphorylation of p53. Although cyclin B(1)-dependent protein kinases can phosphorylate small peptides containing the Ser315 site, cyclin A-cdk2 does not phosphorylate such small peptides suggesting that additional determinants are required for cyclin A-cdk2 interaction with p53. Peptide competition studies have localized a cyclin A interaction site to a Lys381Lys382Leu383Met384Phe385 sequence within C-terminal negative regulatory domain of human p53. An alanine mutation at any one of four key positions abrogates the efficacy of a synthetic peptide containing this motif as an inhibitor of cyclin A-cdk2 phosphorylation of p53 protein. Single amino acid mutations of full-length p53 protein at Lys382, Leu383, or Phe385 decreases cyclin A-cdk2 dependent phosphorylation at Ser315. Cyclin B(1)-cdk2 complexes are not inhibited by KKLMF motif-containing peptides nor is p53 phosphorylation by cyclin B-cdk2 reduced by mutation of the cyclin A interaction site. These data identifying a KKLMF cyclin A docking site on p53 protein highlight a common cyclin A interaction motif that is shared between the tumour suppressor proteins pRb and p53.
J Mol Biol 2000 Jul 14
PMID:The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A. 1088 47

An initiating role for RAS oncogene mutation in several epithelial cancers is supported by its high incidence in early-stage tumors and its ability to induce proliferation in the corresponding normal cells in vitro. Using retroviral transduction of thyroid epithelial cells as a model we ask here: (i) how mutant RAS can induce long-term proliferation in an epithelial cell in contrast to the premature senescence observed in fibroblasts; and (ii) what is the "clock" which eventually triggers spontaneous growth arrest even in epithelial clones generated by mutant RAS. The early response to RAS activation in thyroid epithelial cells showed two features not seen in fibroblasts: (i) a marked decrease in expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1) and (ii) the absence of any induction of p21(waf1). When proliferation eventually ceased (after up to 20 population doublings) this occurred despite undiminished expression of mutant RAS and was tightly correlated with a return to the initial high level of p27(kip1) expression, together with the de novo appearance of p16(ink4a). Importantly, neither the CDKI changes nor the proliferative life span of RAS-induced epithelial clones was altered by induction of telomerase activity through forced expression of the catalytic subunit, hTERT, at levels sufficient to immortalize human fibroblasts. These data provide a basis for cell-type differences in sensitivity to RAS-induced proliferation which may explain the corresponding tumor-type specificity of RAS mutation. They also show for the first time in a primary human cell model that a telomere-independent mechanism can limit not only physiological but also oncogene-driven proliferation, pointing therefore to a tumour suppressor mechanism additional, or alternative, to the telomere clock.
Mol Cell Biol 2000 Aug
PMID:Evidence for a telomere-independent "clock" limiting RAS oncogene-driven proliferation of human thyroid epithelial cells. 1089 5

The Wilms' tumour suppressor gene WT1 is essential for the normal development of the genitourinary system. It appears to play a role in both transcriptional and post-transcriptional regulation of certain cellular genes. However, the mechanisms behind WT1 function are not clearly understood despite the identification of numerous potential target genes and the isolation of several WT1-binding proteins. This study therefore sets out to identify other WT1-associating proteins to help to unravel how WT1 interacts with the cellular machinery. We report the identification of a novel human WT1-associating protein, WTAP, which was isolated using the yeast two-hybrid system. Both in vitro and in vivo assays have shown that the interaction between WTAP and WT1 is specific and occurs endogenously in cells. The mouse homologue of WTAP was isolated and found to be >90% conserved at the nucleotide and protein levels. The human and mouse genes were mapped using fluorescence in situ hybridization to regions in chromosomes 6 (which is thought to harbour a tumour suppressor gene) and 17, respectively. The expression pattern of WTAP was investigated and shown to be ubiquitous, perhaps reflecting a housekeeping role. WTAP is a nuclear protein, which like WT1 localizes throughout the nucleoplasm as well as in speckles and partially co-localizes with splicing factors. Although the significance of this interaction is not yet known, WTAP promises to be an interesting WT1-binding partner.
Hum Mol Genet 2000 Sep 22
PMID:Identification of WTAP, a novel Wilms' tumour 1-associating protein. 1100 26

The tumour suppressor gene p16/INK4a encodes a specific inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. p16/INK4a prevents the association of CDK4 with cyclin D1, and subsequently inhibits phosphorylation of retinoblastoma tumour suppressor protein (pRb), thus preventing exit from the G1 phase. In human cancers, the estimated frequency of genetic alteration involving the p16/INK4a locus is believed to be second only to alteration of p53. A high frequency (greater than 50%) of homozygous p16/INK4a gene deletion has been demonstrated in glioblastoma tissues and p16/INK4a is altered in 80% of glioma cell lines. Therefore, restoration of p16/INK4a would suppress cell proliferation and induce cell growth arrest. We showed here that restoration of p16/INK4a expression in p16 negative U87MG, U251MG and partially deleted U373MG by Ad-CMV-p16/INK4a induced growth suppression in vitro and in vivo. Expression of p16 transferred by Ad-CMV-p16/INK4a in glioma cells was highly efficient and maintained for more than seven days. In addition, we found that the endogenous status of p16 and Rb might affect the expression of exogenous p16/INK4a gene and inhibitory effect of cell proliferation. Even though, there were several factors affecting the efficiency of Ad-CMV-p16/INK4 gene transfer, our results suggest that Ad-CMV-p16 gene therapy strategy is potentially useful and warrants further clinical investigation for the treatment of gliomas.
Int J Mol Med 2000 Nov
PMID:Growth inhibitory effect on glioma cells of adenovirus-mediated p16/INK4a gene transfer in vitro and in vivo. 1102 24

Oral squamous carcinogenesis is a multistep process in which multiple genetic events occur that alter the normal functions of oncogenes and tumour suppressor genes. This can result in increased production of growth factors or numbers of cell surface receptors, enhanced intracellular messenger messenger signalling, and/or increased production of transcription factors. In combination with the loss of tumour suppressor activity, this leads to a cell phenotype capable of increased cell proliferation, with loss of cell cohesion, and the ability to infiltrate local tissue and spread to distant sites. Recent advances in the understanding of the molecular control of these various pathways will allow more accurate diagnosis and assessment of prognosis, and might lead the way for more novel approaches to treatment and prevention.
Mol Pathol 2000 Aug
PMID:Molecular pathogenesis of oral squamous carcinoma. 1104 Sep 37

The cyclin-dependent kinase (cdk) inhibitor, p57 (Kip2) is a tumour suppressor candidate and a paternally-imprinted gene. In humans, the p57(Kip2) gene is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome. From analysis of p57(Kip2)-deficient mice, we demonstrate the relationship between trophoblastic abnormalities and p57(Kip2). Both p57(Kip2) null ((-/-)) embryos and heterozygous embryos with a maternally-derived mutated allele ((+*/-)) displayed placentomegaly, as well as dysplasia of labyrinthine and spongiotrophoblasts. The number of labyrinthine trophoblasts of homozygous embryos was twice that in wild-type embryos. When we measured kinase activities of cdk in total placenta lysates by the immuno complex kinase assay, there were no differences among the genotypes. These results show that p57(Kip2) may function in the proper development of labyrinthine and spongiotrophoblasts by pathways that are not involved with regulation of cdk activities. It is, therefore, suggested that p57(Kip2) protein might have an unknown role.
Mol Hum Reprod 2000 Nov
PMID:p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. 1104 65

Geminiviruses are plant DNA viruses with a small genome that infect a large variety of plant species. Viral proteins regulate viral DNA replication and transcription. Also they appear to have an impact on cellular gene expression. Cellular proteins directly involved in DNA replication, such as PCNA, have long been known to accumulate in cells expressing Rep tomato golden mosaic geminivirus. This effect can be a direct effect of the viral protein and/or be mediated by interference with the G1/S transition control, namely the pathway controlled by the retinoblastoma-related (RBR) protein, analogous to the human retinoblastoma (RB) tumour suppressor protein. Different geminiviruses seem to have evolved two mechanisms to interact with plant RBR proteins. One is dependent on a LxCxE amino acid motif present in proteins, such as RepA, encoded by members of the Mastrevirus genus, and another seems to be mediated by the viral Rep protein, which lacks the LxCxE motif, encoded by members of the Begomovirus, and perhaps the Curtovirus genus. These and other aspects of the relationships between geminivirus replication and cell cycle control pathways will be discussed.
Plant Mol Biol 2000 Aug
PMID:Geminiviruses and the plant cell cycle. 1108 75


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