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 tumour suppressor gene has been shown to be frequently mutated in a wide range of human neoplasms. This is accompanied by increased levels of p53 protein which become immunologically detectable in pathological material. We have investigated the possibility that the differential diagnosis between reactive and neoplastic mesothelium might be resolved using a polyclonal serum raised to human p53 protein, CM-1. None of 20 cases of reactive mesothelial proliferation showed p53 immunoreactivity while 70% (14 of 20) of cases of malignant mesothelioma showed p53 staining. We can thus infer that abnormalities of p53 appear to be a common event in malignant mesothelioma and that p53 immunostaining may be of value in the distinction of malignant mesothelioma from reactive hyperplasia.
 ...
PMID:p53 expression is common in malignant mesothelioma. 139 35

The RB and p53 tumour suppressor genes encode nuclear proteins that exert an inhibitive effect on cell growth. A large variety of human tumour types manifest loss or mutation of the RB or p53 genes, and p53 mutation is the commonest genetic alteration found in tumour cells. In addition, the RB and p53 proteins may be inactivated by complex formation with viral oncoproteins--for instance, in the case of cervical carcinoma carrying human papilloma virus. In vivo introduction of an intact RB or p53 gene into malignant cells lacking the respective gene results in suppression of the neoplastic phenotype and thus of tumourigenicity, p53 being the more potent of the two in this respect. Further elucidation of tumour suppressor genes may well result in future improvement in the diagnosis and treatment of cancer.
 ...
PMID:[Tumor suppressor genes: mutations in RB and p53 genes are significant carcinogenic factors]. 140 28

Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) can have pleiotropic effects on different cell types. M1 myeloid leukaemic cells respond to IL-6 with activation of a terminal differentiation programme which includes activation of genes for certain haemopoietic regulatory proteins (IL-6, IL-1 alpha, IL-1 beta, granulocyte-macrophage colony-stimulating factor [GM-CSF], M-CSF, tumour necrosis factor and transforming growth factor [TGF] beta 1) and for receptors for some of these proteins, thus establishing a network of positive and negative regulatory cytokines. IL-6 and some other cytokines also induce during differentiation sustained levels of transcription factors that can regulate and maintain gene expression in the differentiation programme. M1 leukaemic cells induced to differentiate with IL-6 undergo programmed cell death (apoptosis) on withdrawal of IL-6, and can be rescued from apoptosis by IL-6, IL-3, M-CSF, G-CSF or IL-1, but not by GM-CSF. These differentiating leukaemic cells can also be rescued from apoptosis by the tumour promoter TPA (12-O-tetradecanoylphorbol-13-acetate) but not by the non-tumour-promoting isomer 4-alpha-TPA, and rescue from apoptosis can be achieved by different pathways. Apoptosis can also be induced in undifferentiated M1 leukaemic cells by expression of the wild-type form of the tumour suppressor p53 protein and IL-6 can rescue the cells from this wild-type p53-mediated apoptosis. There are clones of M1 cells that differentiate with IL-6 but not with LIF and another M1 clone that differentiates with either IL-6 or LIF. Differentiation induced by IL-6 or LIF is inhibited by TGF-beta 1. The pleiotropic effects of LIF, like those of IL-6, are presumably also in a network of interacting regulatory proteins.
 ...
PMID:Regulation of leukaemic cells by interleukin 6 and leukaemia inhibitory factor. 142 20

The multistep development of haematopoietic malignancies, like other neoplasms, reflects sequential mutations that either activate proto-oncogenes or disrupt tumour suppressor genes. In a few spontaneous leukaemias or lymphomas, more than one mutation has now been identified, and the experimental analysis of oncogene co-operation is advancing rapidly via retroviral gene delivery and characterization of transgenic mice bearing oncogenes. In transgenic models, tumorigenesis can be accelerated by introducing another oncogene or by using a retrovirus as an insertional mutagen to identify cellular genes that collaborate with the transgene. Leukaemogenesis can be promoted by some ten pairs of oncogenes. The myc nuclear oncoprotein, for example, can collaborate with cytoplasmic oncoproteins such as ras, raf, bcl-2, pim-1 and v-abl, as well as with nuclear products such as bmi-1 or the tumour suppressor p53. The genes in such partnerships seem to provide complementary functions. For example, myc seems to prevent cells from becoming quiescent, whereas bcl-2 blocks programmed cell death; and others, for example ras, may diminish growth factor requirements. The products of genes that collaborate may lie on separate signal transduction pathways, leading to distinct nuclear targets. Key targets are postulated to be regulators of the cell cycle, especially the cyclins and associated kinases that govern progression in the G1 phase.
 ...
PMID:Oncogene co-operation in leukaemogenesis. 145 Nov 8

Inactivation of tumour suppressor genes may be an important aetiological factor in many human cancers including breast. In a study of 197 breast cancer patients, tumour tissue was snap-frozen at the time of surgery and immunohistochemical labelling for p53 protein and retinoblastoma (Rb) gene product carried out using an indirect immunohistochemical technique. Tumours were scored by two independent observers for the intensity of nuclear staining for each antibody. Expression of p53 protein showed a significant association with a shorter time to relapse (P = 0.03) and death (P = 0.02) (log rank test). p53 expression did not correlate with nodal status but showed a significant association with high tumour grade (P = 0.001). Rb gene expression showed no relationship to relapse or survival but loss of expression showed a significant correlation with positive lymph node status. The manner by which these proteins might act to determine tumour behaviour remains to be established.
 ...
PMID:Retinoblastoma and p53 gene expression related to relapse and survival in human breast cancer: an immunohistochemical study. 145 67

The p53 tumour suppressor protein is phosphorylated by several protein kinases, including casein kinase II. In order to understand the functional significance of phosphorylation by casein kinase II, we have introduced mutations at serine 386 in mouse p53, the residue phosphorylated by this kinase, and investigated their effects on the ability of p53 to arrest cell growth. Replacement of serine 386 by alanine led to loss of growth suppressor activity, while aspartic acid at this position partially retained suppressor function. These data suggest that the anti-proliferative activity of p53 is activated by phosphorylation at serine 386, and establish a direct link between the covalent modification of a growth suppressor protein and regulation of its activity in mammalian cells.
 ...
PMID:Mutation of the casein kinase II phosphorylation site abolishes the anti-proliferative activity of p53. 145 21

The tumour suppressor gene p53, located on the short arm of chromosome 17, encodes for a nuclear protein which regulates cell proliferation by inhibiting cells entering S-phase. p53 mutations are alleged to be the commonest genetic abnormality in human cancer. We studied mutant p53 oncoprotein expression, using PAb1801 monoclonal antibody immunohistochemistry, in 25 'ideal' keratoacanthomas and 26 well-, 19 moderately and 18 poorly differentiated squamous cell carcinomas of the skin. While there was a highly significant trend in the proportion of p53 oncoprotein-positive lesions from keratoacanthomas to poorly differentiated squamous cell carcinomas (chi 2 = 17.13, df = 1, exact P = 0.00003), p53 expression was inadequate for distinguishing keratoacanthoma from well-differentiated squamous cell carcinoma (chi 2 = 2.55, df = 1, exact P = 0.18; corresponding to a sensitivity of 0.84 and a specificity of only 0.36).
 ...
PMID:Mutant p53 oncogene expression in keratoacanthoma and squamous cell carcinoma. 833 63

The cellular phosphoprotein p53 inhibits progression through the mammalian cell cycle. Both p53 alleles are frequently mutated in human tumours, indicating that p53 is a tumour suppressor. Recent studies have suggested that p53 functions as a transcriptional activator, but the significance of this activity in cell-cycle control has not been established. The adenovirus 2 (Ad2) early 1B (E1B) 55K protein binds to p53 in transformed cells and contributes to oncogenic transformation by Ad2 (refs 10-12). Here we report that mutants of E1B 55K and wild-type Ad12 E1B 54K proteins show a strong correlation between their ability to inhibit p53-mediated transcriptional activation and their ability to cooperate with adenovirus E1A protein in the transformation of primary cells. These results indicate that p53 probably inhibits cell cycling by functioning as a transcription factor.
 ...
PMID:Inhibition of p53 transactivation required for transformation by adenovirus early 1B protein. 153 43

Wild-type and mutant p53 proteins exhibit opposing activities in respectively suppressing and promoting tumour development. In a rat embryo fibroblast cell line transformed with a murine temperature-sensitive p53 gene, p53 functions as a oncogene at 37 degrees C and as a tumour suppressor at 32 degrees C [Michalovitz, D., Halevy, O. & Oren, M. (1990). Cell, 62, 671-680]. We have used this cell line to investigate whether this temperature-dependent switching of function involves changes in the phosphorylation of p53 protein. Monoclonal antibodies PAb246 and PAb240 were used to immunoprecipitate metabolically 32P-labelled p53 protein in the 'wild-type' or mutant conformation from cells grown at 32 degrees C or 37 degrees C. Tryptic phosphopeptide maps were prepared from the isolated 'wild-type' and mutant p53 proteins. At 32 degrees C and 37 degrees C phosphopeptide maps of the 'wild-type' and mutant protein were identical. This demonstrates that the temperature-dependent conformation change, and associated functional change, in the p53 protein does not involve a change in the state of phosphorylation.
 ...
PMID:The conformational change of a murine temperature-sensitive p53 protein is independent of a change in phosphorylation status. 163 Aug 25

The development of Friend virus induced murine erythroleukaemia is associated with specific genetic events. One of these events is loss of wild type p53 expression, which can occur by internal deletion or proviral insertion in the p53 gene and by single point mutations in the coding sequence. In all cases, the corresponding wild type allele is absent. The high frequency of observed p53 mutations strongly suggests that inactivation of p53 may be an obligatory step in the development of Friend disease. Further evidence that abrogation of normal p53 expression contributes to the development of malignant clones was provided by in vitro reconstitution experiments in Friend cell lines: whereas exogenous mutant p53 was stably expressed in p53 negative FCLs, long term wild type p53 expression was not detected. Friend erythroleukaemia arises as a late consequence of infection of susceptible mice with Friend virus. In addition to p53 gene mutations, proviral insertions occur frequently adjacent to one of two cellular genes, Spi-1/PU.1 or Fli-1. Aberrant expression of these genes may therefore be involved in virus induced erythroleukaemia. Interaction of SFFV env gp55 with the EPO-R also appears to be important in providing a mitogenic signal to infected cells. The order in which these events occur and whether the order is relevant to the progression of the disease are not known. Investigation of the stepwise appearance of these events could provide information on the possible interactions of the gene products involved. Abrogation of normal p53 expression is not restricted to Friend erythroleukaemia: the observation of p53 mutations and allele loss in human breast, lung, colon and hepatocellular carcinomas and in leukaemia suggests that mutation of p53 may be the most common genetic abnormality detected in human cancer (reviewed in this issue). Studies of p53 expression in FCLs provided an early indication that p53 was a tumour suppressor gene. Further studies of the mechanisms by which wild type and mutant p53 affect the growth of p53 negative FCLs may reveal important biochemical properties of p53 in relation to cell cycle control and differentiation of erythroid cells.
 ...
PMID:Friend virus induced murine erythroleukaemia: the p53 locus. 163 45


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