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 inducible response of the tumour suppressor gene p53 has been examined following exposure to DNA-damaging agents in Ataxia telangiectasia (AT) cell lines, an autosomal recessive disorder with multiple clinical and biological abnormalities including sensitivity to ionising radiation. The p53 induction was significantly delayed and reduced in the 8 AT cell lines examined over the 6 h following irradiation with no dose response in p53 induction being observed compared to control cells. The increase of WAF1/CIP1(p21) and GADD45 mRNA, two genes transcriptionally activated by p53, was also reduced in the AT cell lines after such treatment. In contrast, the increase in p53 protein, WAF1/CIP1(p21) and GADD45 mRNA expression following exposure to the alkylating agent methylmethane sulphonate (25 and 100 micrograms ml-1) was similar in both cell types. No alterations in the expression of EBNA-5, an EBV-encoded nuclear antigen which has been shown to bind p53 or mutations in the p53 gene (exons 4 to 8) were found in the AT cell lines studied. The AT gene product would thus appear to be involved upstream of p53, GADD45 and WAF1/CIP1 (p21) in the signalling of the presence of strand breaks produced by ionising radiation, with this defect in response contributing to the high cancer risk and radiosensitivity observed in this disorder.
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PMID:The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. 747 67

Epstein-Barr virus (EBV) efficiently converts resting human B cells into actively cycling, immortal, lymphoblastoid cell lines (LCLs). Here we show that LCLs expressing the full complement of latent viral genes are very sensitive to DNA-damaging agents such as cisplatin. The response includes a rapid accumulation of the tumour suppressor protein p53 and induction of the cellular genes mdm2 and WAF1/p21. Although the levels of Bcl2 protein and Bax mRNA appear unaltered by the activation of p53, within 24 h the majority of cells undergo apoptosis. Over-expression of wild-type p53 in an LCL also resulted in apoptosis; this was preceded by the dephosphorylation of the retinoblastoma gene product, pRb. Primary resting B cells showed no response to cisplatin and even after drug treatment, p53 remained undetectable. However, after infection with EBV, p53 gene expression was induced to a similar level to that found in mitogen-activated B cells. When the physiologically activated primary B cells were exposed to cisplatin, although p53 accumulated as in LCLs, the outcome was growth-arrest rather than gross cell death. We conclude that, in contrast to the transformation of fibroblasts by adenovirus, SV40 or HPV, when B cells become activated and immortalized by EBV they are sensitized to the p53-mediated damage response. When the resulting LCLs are treated with genotoxic agents such as cisplatin, they are unable to arrest like normal cells because they are driven to proliferate by EBV and consequently undergo apoptosis.
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PMID:Epstein-Barr virus efficiently immortalizes human B cells without neutralizing the function of p53. 772 16

Normally growing cells promptly cease DNA synthesis when exposed to genotoxic stresses, such as radiation, and this cell-cycle arrest prevents the accumulation of mutations. The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system, inhibits cell growth, and manifests tumour-suppressor activities. Here we show that mouse embryonic fibroblasts (EFs) lacking IRF-1 are deficient in their ability to undergo DNA-damage-induced cell-cycle arrest. A similar phenotype has been observed in EFs lacking the tumour suppressor p53 (refs 8, 9), although the expression of IRF-1 and p53 are independent of one another. Furthermore, we show that transcriptional induction of the gene encoding p21 (WAF1, CIP1), a cell-cycle inhibitor, by gamma-irradiation is dependent on both p53 and IRF-1, and that the p21 promoter is activated, either directly or indirectly, by both in a transient cotransfection assay. These two tumour-suppressor transcription factors therefore converge functionally to regulate the cell cycle through the activation of a common target gene.
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PMID:Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage. 875 76

Mutations in the p53 tumour suppressor gene are the most common genetic alteration found in human cancers. Most of them are accompanied by stabilization of the protein, which renders it detectable through immunohistochemical techniques. Although p53 expression is a very common finding in Hodgkin's disease (HD), the status of the p53 gene is scarcely known, due to the difficulty in sequencing this gene in a lesion in which tumour cells are thought to constitute a very minor subpopulation, diluted in a background of supposedly benign cells. The pattern of expression of two downstream p53 proteins (MDM2 and p21 WAF1/CIP1, was studied as an indirect way of assessing p53 gene status. MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes. MDM2 and p21WAF1/CIP1 immunostaining was detected in all the cases analysed, independently of histological type, and were mainly present in Sternberg-Reed and Hodgkin (H & SR) cells. These immunohistochemical results were confirmed by Western blotting. To study the cause of MDM2 protein accumulation, MDM2 mRNA expression was also investigated by reverse transcription polymerase chain reaction (RT-PCR). The results show the presence of MDM2 transcripts in all cases of HD, albeit at lower levels than those found in reactive lymphoid tissue. These results seem to support the hypothesis that p53 is transcriptionally active in at least some of the H & SR cells in HD, and is able to induce MDM2 and p21WAF1/CIP1 protein expression.
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PMID:MDM2 and p21WAF1/CIP1, wild-type p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's disease. 894 16

The p53 tumour suppressor gene is a cell cycle regulator, able to induce cell cycle arrest to allow DNA repair or apoptosis. The molecular mechanisms underlying p53 action imply transactivation of p53 dependent genes such as WAF1 (for wild type p53 associated fragment 1) and the murine double minute (MDM2) gene. In some cases, inactivation of the p53 gene results from p53 gene mutations leading to p53 protein accumulation, but in others it may results from mechanisms other than mutation, such as interaction with viral or cellular proteins. The expression of p53 protein and p53 transactivated gene proteins p21/WAF1 and MDM2, combined with in situ detection of apoptosis, was studied in specimens of CMV-infected patients as an in vivo model of p53 alteration not due to point mutation. p53 positivity was found in CMV + cells in different tissues, in cells with typical inclusion bodies, and in in situ hybridization and immunohistochemistry CMV + cells without inclusions (hidden infection). Although this p53 reactivity was accompanied by the expression of MDM2 and p21/WAF1 proteins, the patterns of MDM2 and p21/WAF1 protein expression were mutually exclusive, and were associated with the presence or absence of inclusion bodies. Nuclei bearing inclusion bodies were usually MDM2+, p21/ WAF1-, while hidden infected cells were usually MDM2-, p21/WAF1+. Apoptosis was not detected in any tissue section from CMV-infected patients. Two alternative patterns were found in CMV-infected tissues: p53+, p21/WAF1+, MDM2-, or p53+, p21/WAF1-. MDM2+ protein expression. These may represent examples of p53 dependent alternative effects in the course of CMV infection. Early stages are represented by CMV + cells without inclusion bodies, which display p53 and p21/ WAF1 expression, suggesting that p53 could be acting as a growth suppressor protein. Late CMV infection is represented by cells harbouring inclusion bodies. These cells showed a p53+, p21/WAF1-, MDM2+ profile, consistent with MDM2 mediated p53 inactivation. The absence of p21/WAF1 expression and lack of apoptosis suggest that the p53 protein expressed by MDM2+ cells could be functionally inactivated in CMV-infected cells with inclusion bodies. Previous studies have suggested that p53 inactivation by MDM2 over-expression occurs in sarcomas and lymphomas. Our observations seem to indicate that this mechanism of MDM2 mediated p53 inactivation may play a role in the late phase of CMV infection.
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PMID:p53 expression in CMV-infected cells: association with the alternative expression of the p53 transactivated genes p21/WAF1 and MDM2. 906 34

Many tumour therapies act by inducing a cellular damage response pathway mediated by the tumour suppressor protein p53. Alternative outcomes of p53 induction include apoptosis or transient cell-cycle arrest, both thought to require the transcriptional activity of wild-type p53. Current research highlights the action of a p53-activated gene, p21Cip1/WAF1/Sdi1, which encodes a cyclin-kinase inhibitor important in mediating p53-dependent cell-cycle arrest, while programmed cell death in response to DNA damage requires transcriptionally active p53 but not activation of p21Cip1/WAF1/Sdi1. This review examines the roles of p53 and p21Cip1/WAF1/Sdi1 in controlling cell proliferation, in the light of a new study on expression of p53 and p21Cip1/WAF1/Sdi1 in squamous cell carcinoma of the larynx.
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PMID:Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21Cip1/WAF1/Sdi1. 939 24

While cellular transformation by small DNA tumour viruses usually involves targeting the product of the p53 tumour suppressor gene by a virally encoded protein, none of the three polyoma virus (Py) specified T antigens have been observed to interact with p53. We show that primary mouse embryo fibroblasts and REF52 cells, which resemble primary cells in requiring co-operating oncogenes for transformation, cannot be transformed by the Py oncogene, middle T-antigen (PyMT), alone. These cells can be transformed by the complete Py early region, which encodes the Py large, middle and small T-antigens. We find that PyMT can transform rodent cells lacking a functional p53 protein (p53 null mouse embryo fibroblasts and DN-REF52 cells which contain a dominant negative p53). In Py transformed REF52 cells (Py-REF52) there is no significant accumulation of p53 protein, as opposed to SV40 transformed REF52 cells (SV-REF52) in which the amount of steady state p53 protein is elevated. However accumulation of p53 is observed following exposure of Py-REF52 cells to u.v. Treatment of Py-REF52 cells with X-rays results in a rapid increase in the levels of the p53-induced proteins p21/WAF1 and MDM2. In untransformed REF52 cells, X-irradiation causes p53 activation, which results in induction of both G1/S and G2/M blocks. In SV-REF52 and DN-REF52 cells, p53 abrogation results in the absence of both the G1/S and G2/M blocks. Only the absence of a G1/S block is observed in Py-REF52 cells exposed to X-irradiation. Together these results indicate that in contrast to most other DNA tumour viruses, Py does not appear to interfere with the DNA damage induced transactivation activities of the p53 protein but absence of a functional p53 protein can mediate transformation by the PyMT oncogene in the absence of other co-operating oncogenes. Possible modes of transformation by Py are discussed.
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PMID:p53 in polyoma virus transformed REF52 cells. 944 59

p16MTS1/CDKN1 and the retinoblastoma protein Rb are both involved in negative regulation of G1/S progression in the mammalian cell cycle. Inactivation of one of these tumour suppressor genes is involved in many malignant tumours, and in some studies a negative correlation of p16 and Rb expression has been found. In order to study this interaction in endometrial carcinogenesis, we investigated 36 endometrial carcinomas, 11 cases of hyperplasia, 23 normal endometrial samples, and two uterine carcinoma cell lines by immunohistochemistry or RT-PCR. Rb was expressed in normal endometrial epithelium, hyperplasia, cell lines, and most carcinomas; negative immunostaining was only detected in 1 of 36 tumours. In contrast, p16 expression was weak in normal endometrium and increased in most cases of hyperplasia, but negative or minimally positive in 74% of the carcinomas and the Hec1B adenocarcinoma cell line, and there was no significant association with Rb immunostaining. Strikingly high p16 expression was found in foci of squamous metaplasia within hyperplastic or carcinomatous tissue. Deletion and mutation analysis of the p16 gene was performed in DNA from microdissected tumour samples and cell lines. No p16 deletion was found, and mutations were detected in only one tumour sample and Skut1B uterine mixed mesodermal tumour cells. Our data indicate that in spite of low or absent p16 expression, genetic alterations of the p16 and Rb tumour suppressor genes are rare in endometrial carcinogenesis.
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PMID:P16/MTS1 and pRB expression in endometrial carcinomas. 1007 Dec 31

The role and prognostic value of the tumour suppressor p21/WAF1 expression in epithelial ovarian cancer has not yet been defined. Therefore, the expression of p21/WAF1 was assessed immunohistochemically (IHC) in 316 epithelial ovarian malignancies in relation to p53, cell proliferation and patient survival. p21/WAF1 expression was inversely correlated with p53 and cell proliferation. Low p21/WAF1 expression was significantly associated with high grade of the tumour (P = 0.0005), advanced FIGO stage (P = 0.001) and primary residual tumour (P = 0.0001). Low p21/WAF1 expression was a marker of poor overall survival (P = 0.012). Similarly, p53-positivity and high cell proliferative activity were significant predictors of poor survival in univariate analyses. Moreover, the patients with p21-/p53+ tumours had a poorer overall (P < 0.00005) and recurrence-free (P = 0.0005) survival in univariate analyses, and the p21/p53 expression independently predicted tumour recurrence in Cox's multivariate analysis. Our results suggest that p21/WAF1 expression is mostly p53-dependent in epithelial ovarian cancer. High p21/WAF1 expression seems to function as a negative cell cycle regulator and as a marker of favourable disease outcome in epithelial ovarian cancer. In addition, the patients with their tumour expressing no or low p21/WAF1 protein but positive for p53 had a notably higher risk of recurrent disease, implicating that these patients might be more prone to treatment failures.
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PMID:p21/WAF1 expression as related to p53, cell proliferation and prognosis in epithelial ovarian cancer. 1020 7

Ataxia-telangiectasia mutated (ATM) is the product of the gene mutated in the human genetic disorder ataxia-telangeictasia (A-T). It is a 370 kDa protein that is a member of the phosphatidyl inositol 3-kinases superfamily. A-T cells and those derived from Atm-/- mice are characterized by hypersensitivity to ionizing radiation and defective cell cycle checkpoints. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation including the G1/S interface where ATM plays an important role in the activation of the tumour suppressor gene product p53. Activation leads to the induction of p21/WAF1, inhibition of cyclin-dependent kinase activity, failure to phosphorylate key substrates such as the retinoblastoma protein and consequently G1 arrest. ATM also plays an important role in the regulation and surveillance of meiotic progression. Absence of ATM gives rise to a spectrum of defects including immunodeficiency, neurodegeneration, radiosensitivity and cancer predisposition. It is clear that a better definition of the role of ATM in DNA damage recognition, cell cycle control and cell signalling may assist in the treatment of the progressive neurodegeneration in this syndrome.
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PMID:ATM: the product of the gene mutated in ataxia-telangiectasia. 1046 28


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