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)

This study attempts to define more clearly the morphology and ultrastructure of mummified Hodgkin cells, to determine their incidence in the different histological subtypes of Hodgkin's disease (HD), and to correlate these data with the expression of p53, bcl-2, mdm2, and p21/WAF1. Forty-five cases of primary HD were examined at light and electron microscopic level. DNA strand breaks were detected by the in situ end-labelling (ISEL) and the TdT-mediated dUTP-digoxigenin nick end-labelling (TUNEL) technique. Mummified Hodgkin cells display morphological features that differ from those of classical apoptosis. In contrast to apoptotic cells, mummified Hodgkin and Reed-Sternberg (HRS) cells do not react in the ISEL or TUNEL procedures and maintain the expression of antigens such as CD30 and CD15. The morphology of mummified tissue cells could be simulated by CD95-mediated induction of apoptosis in the Hodgkin cell line HDLM2 if internucleosomal DNA fragmentation was inhibited by zinc ions. The highest incidence of mummified cells was found in the nodular sclerosis and mixed cellularity subtypes, whereas the lowest frequency was observed in nodular paragranuloma. The frequency was independent of p53, bcl-2, p21, and mdm2 expression. p21 and mdm2 immunoreactivity of HRS cells was correlated with p53 status. HRS cells in nodular paragranuloma were virtually negative for p21/WAF1 or bcl-2. Classical apoptotic cells reacting in the TUNEL and ISEL procedures are found in all subtypes of HD and are derived from the non-neoplastic cellular background. In conclusion, mummified Hodgkin cells display features of apoptosis lacking the internucleosomal DNA fragmentation. The pattern of the p53-transactivated genes mdm2 and p21/WAF1 suggests that inactivating mutations of p53 are rare in HD.
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PMID:The mummified Hodgkin cell: cell death in Hodgkin's disease. 934 31

Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn2+ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25 degrees C and 9.8 kcal/mol at 10 degrees C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions.
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PMID:Thermodynamic stability of wild-type and mutant p53 core domain. 940 13

The WAF1/p21 gene product is an inhibitor of cyclin-dependent kinases which can be induced by the tumor suppressor p53 and mediate some of its effects, or function in p53-independent pathways of cell cycle regulation. Although a potential tumor suppressor gene, WAF1/p21 is expressed in bladder cancer. To elucidate the function of p21 in tumor cells we have investigated in urothelial carcinoma cell lines: i) WAF1/p21 mRNA and protein expression, ii) the biological effects of p21 overexpression or down-regulation and (iii) whether p21 can be induced by p53. WAF1/p21 mRNA levels examined in four cell lines were comparable to bladder mucosa. One cell line, HT1376, failed to express p21 protein due to a frame shift mutation. Overexpression of WAF1/p21 cDNA inhibited clone formation in three cell lines, whereas transfection with antisense WAF1 increased clone sizes and numbers. WAF1 sense clones showed diminished cell proliferation compared to the parental cell line. Apoptosis- induced wild-type p53 was not inhibited by overexpression of antisense WAF1/p21. In a cell clone derived from line VMCub1 by stable transfection with wild-type p53 under the control of a metallothionein promotor, p21 was induced along with p53 upon activation of the promoter with zinc chloride. This induction was accompanied by a decrease in cell proliferation but by little apoptosis. These data suggest that p21 inhibits proliferation in a p53-dependent or independent manner but does not mediate p53-induced apoptosis in urothelial carcinoma cells.
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PMID:WAF1/p21 regulates proliferation, but does not mediate p53-dependent apoptosis in urothelial carcinoma cell lines. 947 2

S100B(beta beta) was found to interact with the tumor suppressor protein, p53, and inhibit its PKC-dependent phosphorylation and tetramer formation [Baudier, J., Delphin, C., Grunwald, D., Khochbin, S., and Lawrence, J. J. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 11627-11631]. Since PKC-dependent phosphorylation at the C-terminus of p53 is known to effect transcription and p53 tetramer formation [Sakaguchi, K., Sakamoto, H., Lewis, M. S., Anderson, C. W., Erickson, J. W., Appella, E., and Xie, D. (1997) Biochemistry 36, 10117-10124], we examined the interaction of S100B(beta beta) with a peptide derived from the C-terminal regulatory domain of p53 (residues 367-388). In this paper, we report that S100B(beta beta) binds to the p53 peptide (CaK3 < or = 23.5 +/- 6.6 microM) in a Ca(2+)-dependent manner, and that the presence of the p53 peptide was found to increase the binding affinity of Ca2+ to S100B(beta beta) by 3-fold using EPR and PRR methods, whereas the peptide had no effect on Zn2+ binding to S100B(beta beta). Fluorescence and NMR spectroscopy experiments show that the p53 peptide binds to a region of S100B(beta beta) that probably includes residues in the "hinge" (S41, L44, E45, E46, I47), C-terminal loop (A83, C84, H85, E86, F87, F88), and helix 3 (V52, V53, V56, T59). Together these data support the notion that S100B(beta beta) inhibits PKC-dependent phosphorylation by binding directly to the C-terminus of p53.
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PMID:The Ca(2+)-dependent interaction of S100B(beta beta) with a peptide derived from p53. 948 22

In a consecutive series of 222 colorectal carcinomas from patients with a median follow-up time of 56.8 months (range, 0.5-92.2) treated with surgery, the TP53 gene was screened for mutations. Exons 5-8 were analyzed using constant denaturant gel electrophoresis followed by sequencing, and mutations were found in 102 cases (45.9%). Mutations were found more frequently in rectal tumors versus other locations (P = 0.029) and in aneuploid compared to diploid tumors (P < 0.001). Presence of a TP53 mutation was also significantly associated with absence of microsatellite instability (P = 0.028), as well as with loss of heterozygosity at 17p13 (P < 0.001). The TP53 mutations in the left-sided and rectal tumors were more often transversions than transitions, indicating a different etiology in the development of these tumors. The tendency for shorter cancer-related survival among patients with mutations in their tumors was only statistically significant for patients with left-sided tumors (P = 0.003). All patients with mutations affecting the L3 domain of the protein involved in zinc binding had a significantly shorter cancer-related survival (P = 0.036), indicating that mutations affecting this domain have biological relevance in terms of colorectal cancer disease course. These results suggest that knowledge of a patient's TP53 status, with respect to both the presence and the localization of the mutation, may be important in prognosis evaluation, particularly when selecting patients for more aggressive postoperative therapeutic intervention.
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PMID:TP53 and long-term prognosis in colorectal cancer: mutations in the L3 zinc-binding domain predict poor survival. 951 72

The transcription factor p53 controls the proliferation and survival of cells exposed to DNA damage. The specific DNA-binding domain of p53 (residues 102-292) has a complex tertiary structure that is stabilized by zinc. In this study, we showed that exposure of cultured cells to the membrane-permeable chelator N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine induced wild-type p53 to accumulate in an immunologically "mutant" form (PAb240+, PAb1620-) with decreased DNA-binding activity. Removal of N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine from culture medium allowed p53 to refold into the immunologically wild-type form, followed by a transient increase in DNA binding, expression of the cyclin-dependent kinase inhibitor p21WAF1, and cell-cycle delay in the G1 phase. Thus, modulation of intracellular zinc induced conformational changes in p53 that activated wild-type function, suggesting that metalloregulation may play a role in controlling p53.
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PMID:Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. 953 52

WT1 encodes a tumor suppressor that is expressed in cells of the developing kidney and is inactivated in Wilms tumor, a pediatric kidney cancer. The adenovirus E1B 55K gene product contributes to the transformation of primary baby rat kidney (BRK) cells by binding and inactivating the product of the p53 tumor suppressor. We have previously demonstrated that WT1 and p53 are present within a protein complex in vivo. We now show that WT1 is physically associated with E1B 55K in adenovirus-transformed cells, an interaction that is mediated by the first two zinc fingers of WT1. Immunodepletion of p53 abrogates the coimmunoprecipitation of E1B 55K and WT1, consistent with the presence of a trimeric protein complex containing these three proteins. In the presence of E1B 55K, WT1 which is normally localized in the nucleus, is retained within a very high molecular weight complex and sequestered in the characteristic perinuclear cytoplasmic body that contains E1B 55K and p53. Expression of E1B 55K in osteosarcoma cells that undergo apoptosis following expression of WT1 inhibits WT1-mediated cell death. We conclude that E1B 55K may target WT1 along with p53, resulting in the functional inactivation of both tumor suppressor gene products by this viral oncoprotein.
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PMID:E1B 55K sequesters WT1 along with p53 within a cytoplasmic body in adenovirus-transformed kidney cells. 957 85

Recent studies have suggested that different mutation types within the core domain of the tumour suppressor protein p53, i.e. DNA contact mutations and structural mutations, confer different biological properties. We have analysed in 86 head and neck squamous cell carcinomas (HNSCC), whether these p53 mutation types have a differential clinical impact. Thirty-seven missense mutations were identified. Thirteen of these (36%) were DNA contact mutations, occurring in the L3 loop, in the H2 loop sheet helix motif, in the S10 beta strand and in Zinc binding residues. Microsatellite marker analysis revealed a selective association between these mutations and the loss of wild-type alleles (100% LOH vs 50% LOH in tumours with structural mutations; P=0.0034, Fisher's exact, 2-tailed). In comparison to structural mutations or to the absence of mutations in the core domain, DNA contact mutations were associated with higher tumour stages (84.6% vs 62%), a higher incidence of lymph node metastasis (91.7% vs 56%; P=0.014, Fisher's exact, 2-tailed), a shortened recurrence-free survival (8.1 months vs 23.7 months, P=0.047, log rank test) and overall survival (11 months vs 29.2 months; P=0.003, log rank test). The latter was also the case when only stage IV tumours were analysed (P=0.0055, log rank test). These data indicate that in HNSCC, TP53 DNA contact mutations confer a strong selection pressure to eliminate wild-type alleles, and that they result in an accelerated tumour progression and reduced therapeutic responsiveness.
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PMID:TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer. 958 15

Apoptosis, together with proliferation, is a main factor of selection of the clones of developing T-lymphocytes: the clones not supported by positive selection are subject to apoptosis and apoptosis accounts for discarding of potentially autoaggressive clones, i.e., for negative selection in the thymus and peripheral lymphoid tissue. Realization of apoptosis at different stages of the development of T-lymphocytes depends to a varying extent on Fas, Bcl-2, p53, and other regulators. The dendritic cells are the main cell type, the contact with determines apoptosis of T-lymphocytes. A possible role of the epithelial cells was shown in few models (on murine cells) and was not practically studied. We obtained a line of epithelial cells of the human thymus cells HTSC, cocultivation with which induces apoptosis of immature thymocytes and blood T-cells activated by mitogens. Development of apoptosis is suppressed by inhibitors of protein and RNA synthesis, chelators Ca2+, ions Zn2+, and factors destroying the cytoskeleton components. In this model, interaction of pairs of molecules CD4-HLA class II and LFA-1-ICAM-1. When in contact with the HTSC cells, the thymocytes of mice mutant for Fas-receptor (line MRL.lpr) are subject to apoptosis, but when this receptor is present, it affects the development of apoptosis.
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PMID:[Apoptosis and thymocyte development (epithelial cells as inducers of thymocyte apoptosis)]. 960 47

Metallothioneins (MTs) are low molecular weight, zinc-binding proteins that by activating zinc metalloenzymes participate in the regulation of growth and development. The present study was designed to examine the roles of MTs in cell proliferation using an in vivo model of liver regeneration following partial hepatectomy (PH) in rats. The levels of MT-I and MT-II were studied with respect to regulation of proliferative potential, cell cycle checkpoint activity, and oxidative stress in the rat PH model. We synthesized a 17-mer antisense phosphorothioate oligodeoxynucleotide (S-ODN), named aMT, complimentary to the start site of the MT-I mRNA sequence and an appropriate control. Both S-ODNs were administered intraperitoneally at the dose of 5 mg/kg following 70% PH. MT became induced 57.4 +/- 9.8-fold following PH and the said effect became attenuated dramatically following administration of aMT. In addition, PH rats treated with aMT exhibited decreased rate of liver regeneration as measured by expression of proliferating cell nuclear antigen and elevated cell cycle checkpoint activity as determined by expression of p53. The results of these studies suggest that MT isoforms with their high thiol contents do play an important role in cellular functions and especially during stressful states induced by a broad range of mediators generating free radicals.
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PMID:Manipulation of metallothionein expression in the regenerating rat liver using antisense oligonucleotides. 961 77


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