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 analysis of loss of heterozygosity (LOH) in tumours can be a powerful tool for mapping the sites of tumour suppressor genes in the human genome. A panel of breast cancer patients was assembled as pairs of tumour and lymphocyte DNA samples and LOH studies carried out by Southern hybridisation with polymorphic loci mapping to the X chromosome with appropriate controls. Deletion mapping revealed a high frequency of small regionalised deletions, defining at least three independent regions, one of which is particularly well mapped to a 500 kb stretch of DNA in the distal portion of the pseudoautosomal region of Xp. A second region has been identified within the pseudoautosomal region close to the pseudoautosomal boundary, and there is a third discrete site of loss on distal Xq. Perturbations of sequences at these regions represent independent events in a number of patients. This study represents the first detailed analysis of LOH on the X chromosome in human breast tumours, the results of which indicate that at least three regions of this chromosome are involved in the disease.
 ...
PMID:Loss of heterozygosity on the X chromosome in human breast cancer. 754 30

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.
 ...
PMID:Murine models of neoplasia: functional analysis of the tumour suppressor genes Rb-1 and p53. 755 30

One of the most commonly detected abnormalities in human cancer is mutation of the p53 tumour suppressor gene. Intrinsic to the function of p53 is its ability to induce apoptotic cell death and to cause cell cycle arrest. Moreover, p53 plays an important role in controlling the cellular response to DNA damaging agents such as ionizing radiation and cancer chemotherapeutic drugs. Loss of p53 function causes increased resistance to radiation and chemotherapeutic agents, and there is increasing evidence that p53 mutational status is an important determinant of clinical outcome in cancer. This review will focus on recent data describing the biochemistry of p53 function, its role in mediating apoptosis and cell cycle arrest and in the control of tumour growth and death.
 ...
PMID:Apoptosis, cancer and the p53 tumour suppressor gene. 755 31

When growth-arrested mouse fibroblasts re-entered the cell-cycle, the rise in tumour suppressor p53 mRNA level markedly preceded the rise in expression of the p53 protein. Furthermore, gamma-irradiation of such cells led to a rapid increase in p53 protein biosynthesis even in the presence of the transcription inhibitor actinomycin D. Both findings strongly suggest that p53 biosynthesis in these cells is regulated at the translational level. We present evidence for an autoregulatory control of p53 expression by a negative feed-back loop: p53 mRNA has a predicted tendency to form a stable stem-loop structure that involves the 5'-untranslated region (5'-UTR) plus some 280 nucleotides of the coding sequence. p53 binds tightly to the 5'-UTR region and inhibits the translation of its own mRNA, most likely mediated by the p53-intrinsic RNA re-annealing activity. The inhibition of p53 biosynthesis requires wild-type p53, as it is not observed with MethA mutant p53, p53-catalysed translational inhibition is selective; it might be restricted to p53 mRNA and a few other mRNAs that are able to form extensive stem-loop structures. Release from negative feed-back regulation of p53 biosynthesis, e.g. after damage-induced nuclear transport of p53, might provide a means for rapidly increasing p53 protein levels when p53 is required to act as a cell-cycle checkpoint determinant after DNA damage.
 ...
PMID:Negative feedback regulation of wild-type p53 biosynthesis. 755 87

The human tumour suppressor protein p53 is critical for regulation of the cell cycle on genotoxic insult. When DNA is damaged by radiation, chemicals or viral infection, cells respond rapidly by arresting the cell cycle. A G1 arrest requires the activity of wild-type p53, as it is not observed in cells lacking functionally wild-type protein, and at least some component of S phase and G2/M arrests is also thought to be p53-dependent. p53 functions as a transcription factor which binds specific DNA sequences, and recently major downstream targets have been identified, including p21Cip1, an inhibitor of the cell cycle kinases that also blocks the replicative but not the repair function of DNA polymerase delta auxiliary factor, PCNA. Current interest focuses on developing novel cancer therapies based on our knowledge of the activity of p53 and p21Cip1 in the cell cycle.
 ...
PMID:Tumour suppressors, kinases and clamps: how p53 regulates the cell cycle in response to DNA damage. 757 91

Numerous clinical, epidemiological and molecular findings link some types of Human Papillomaviruses (HPV) with cancer of the genital tract. They share a common pathway of transformation with a number of DNA tumour viruses, such as Adenovirus and SV40. Although all these viruses are termed 'DNA tumour viruses' and have similar in vitro transforming activities, Human Papillomavirus is the only one so far clearly involved in human cancer. Extensive studies on HPV E6 and E7 proteins have demonstrated their involvement in malignant transformation. E6 and E7 bind the products of tumour suppressor genes, p53 and Rb1, respectively, modifying or inactivating their normal functions. The Rb1 and p53 genes are deleted or mutated in several cancers and both proteins regulate the transcription of genes involved in cell cycle progression control. The E6/p53 and E7/Rb1 interactions result in a deregulation of the cell cycle with loss of control of crucial cellular events, such as DNA replication, DNA repair and apoptosis.
 ...
PMID:Human papillomavirus E6 and E7: proteins which deregulate the cell cycle. 757 92

Cytogenetic and molecular studies in neuroblastoma suggest the presence of a tumour suppressor gene at the distal chromosome band 1p36. Previously, we hypothesised that a constitutional translocation involving the region 1p36 [t(1;17)(p36;q12-q21)] in a patient with neuroblastoma predisposed him to tumour development. Here we report the molecular delineation of the translocation breakpoints. Somatic cell hybrids containing the derivative chromosomes were used to determine the position of chromosome 1p and 17q DNA probes respective to the breakpoints using fluorescence in situ hybridisation. The 1p breakpoint was localised between the PND and D1S56 loci. The chromosome 17q breakpoint is flanked by NF1 and SCYA7, as proximal and distal marker, respectively. We redefined the translocation as t(1;17)(p36.31-13;q11.2-q12). The identification of flanking markers of the breakpoints is a prerequisite for breakpoint cloning and identification of a putative neuroblastoma suppressor gene.
 ...
PMID:Characterisation of the chromosome breakpoints in a patient with a constitutional translocation t(1;17)(p36.31-p36.13;q11.2-q12) and neuroblastoma. 757 58

For several human tumour types, allelic loss data suggest that one or more tumour suppressor genes reside telomeric to the p53 gene at chromosome 17p13.1. In the present study we have used a new strategy, involving molecular analysis of a DNA site hypermethylated in tumour DNA, to identify a candidate gene in this region (17p13.3). Our approach has led to identification of HIC-1 (hypermethylated in cancer), a new zinc-finger transcription factor gene which is ubiquitously expressed in normal tissues, but underexpressed in different tumour cells where it is hypermethylated. Multiple characteristics of this gene, including the presence of a p53 binding site in the 5' flanking region, activation of the gene by expression of a wild-type p53 gene and suppression of G418 selectability of cultured brain, breast and colon cancer cells following insertion of the gene, make HIC-1 gene a strong candidate for a tumour suppressor gene in region 17p13.3.
 ...
PMID:p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. 758 25

In response to DNA damage, in particular DNA strand breaks, the proposed roles for normal tumour suppressor protein p53 are to increase the period of time available for DNA repair prior to replication, or to direct damaged cells into programmed cell-death. Since treatment of mammalian cells with (+/-)-anti-benzo[a]pyrene diolepoxide [(+/-)-anti-BPDE] --a mixture of metabolites comprising the most reactive (+)-anti-enantiomer of the full environmental carcinogen benzo[a]pyrene--has been shown to result in induction of DNA repair processes and consequently in DNA strand break formation, the aim of the present study was to investigate whether p53 accumulation is induced in (+/-)-anti-BPDE-treated phytohaemagglutinin-stimulated human peripheral blood lymphocytes (PBLs). Both immunocytochemical and immunoblot analysis indicated that treatment of PBLs with (+/-)-anti-BPDE results in p53 accumulation. Optimal accumulation was observed at 2.5 microM, while no increase of p53 levels was observed at concentrations < 2.5 microM and > 10 microM. Further, (+/-)-anti-BPDE-induced p53 accumulation in PBLs was found to be time-dependent with accumulation up to 24 h after the onset of treatment. Treatment of PBLs with 2.5 microM of (+/-)-anti-BPDE and 1 mM of 3-aminobenzamide, an inhibitor of the DNA strand break-dependent enzyme poly(ADP-ribose) polymerase, resulted in increased p53 levels, in comparison to cells treated with (+/-)-anti-BPDE alone. This combination also potentiated the frequency of (+/-)-anti-BPDE-induced micronuclei. These findings suggest that (+/-)-anti-BPDE-induced DNA strand break formation is responsible for the observed p53 accumulation. It is unlikely that poly(ADP-ribose) polymer formation is a prerequisite in the process of p53 accumulation, as triggered by DNA strand-break inducing agents like (+/-)-anti-BPDE. It is hypothesized that p53-dependent pathways may be activated in phytohaemagglutinin-stimulated human peripheral blood lymphocytes exposed ex vivo to (+/-)-anti-BPDE.
 ...
PMID:Inhibition of poly(ADP-ribose) polymerase increases (+/-)-anti-benzo [a]pyrene diolepoxide-induced micronuclei formation and p53 accumulation in isolated human peripheral blood lymphocytes. 758 97

Active unspecific immunotherapy in an adjuvant or palliative setting has been shown to enhance survival in melanoma patients, and gene therapy now offers new perspectives for active specific immunotherapy. Gene therapy includes the transfer of genetic material performed by either viral or non-viral methods and in vivo or ex vivo. For melanoma the following approaches are suggested: vaccination with tumour-specific, HLA-associated antigens using peptides or 'naked DNA', vaccination with melanoma cells transfected with cytokine genes or B7, adoptive immunotherapy with specific T-lymphocytes or transfected tumour-infiltrating lymphocytes, or transfection of tumour cells with a tumour suppressor gene whose dysfunction plays a crucial role in melanoma.
 ...
PMID:[Strategies for gene therapy of melanoma]. 760 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>