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)

In order to define the roles of p53 in acquisition of drug resistance in ATL cell lines, we prepared several ATL cell lines which differed in sensitivity to adriamycin (ADM), and examined their functional p53 statuses, expressions of p53, p21, Bcl-2, Bax, and cell cycles. Our findings demonstrated: (1) Regardless of sensitivity to ADM, most of the cell lines, including ADM-resistant cell lines, carried wild-type p53. (2) Only one cell line, ED-S, which was the most sensitive to ADM carried non-functional mutated-type p53. (3) In the ATL cells carrying wild-type p53, regardless of sensitivity to ADM, ADM-treatment led to an elevation of p53 protein level with concomitant elevations of p21 and Bax protein levels. (4) In the cell line expressing mutated-type p53, ADM-treatment at the concentration of IC50 induced elevations of p53, and Bax protein levels but did not p21 protein level. (5) Expression of Bcl-2 protein did not change in any of the cell lines by treatment with ADM at their respective IC50 levels, but increased in the ADM-resistant cell line when it was treated with ADM at IC50 of its parent cell line. (6) In the cell cycle analysis, ADM-treatment induced G1- and G2-arrest and then apoptosis in the cell lines with wild-type p53, whereas it induced only G2-arrest and then apoptosis in the cell line with mutated-type p53 at the same time course as in those with wild-type p53. These findings suggest that p53 does not play a leading part either in the apoptosis induced by ADM, or in the acquisition of resistance to ADM in ATL cells, and that ADM-induced apoptosis is mediated by multiple pathways leading to the activation of effector molecules.
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PMID:[Roles of p53 in adriamycin-induced cell death and in acquisition of adriamycin resistance in adult T-cell leukemia (ATL) cells]. 1042 67

Nickel (Ni) compounds are potent carcinogens and can induce malignant transformation of rodent and human cells. In an attempt to unravel the molecular mechanisms of Ni-induced transformation we investigated transcriptional activity of hypoxia-inducible factor (HIF-1) and p53 tumor suppressor protein in Ni-transformed cells. We demonstrated that the activity of HIF-1-responsive promoters was increased in Ni-transformed rodent cells resulting in the increased ratio between HIF-1- and p53-stimulated transcription. To further elucidate the roles of HIF-1 and p53 in Ni-induced transformation we used human osteosarcoma (HOS) cells and a Ni-transformed derivative, SA-8 cells. Since non-functional p53 was expressed in both HOS and SA-8 cells, acute Ni treatment induced HIF-1alpha protein and HIF-1-dependent transcription without affecting p53. In MCF-7 and A549, human cancer cells with the wild-type p53, both functional p53 and HIF-1alpha proteins accumulated following exposure to Ni. The induction of HIF-1alpha and wild-type p53 by Ni was detected after 6 h and was most pronounced by 24 h. These results suggest that acute Ni treatment causes accumulation of HIF-1alpha protein and simultaneous accumulation of wild-type, but not mutant, p53. We suggest that the induction of hypoxia-like conditions in Ni-treated cells with subsequent selection for increased HIF-1-dependent transcription is involved in Ni-induced carcinogenesis.
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PMID:Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors. 1046 29

SCH58500 (ACN53) is a recombinant adenovirus expressing human p53 for gene therapy of cancer. In preclinical studies, SCH58500 has shown efficacy against many tumor-types with non-functional p53. This activity arises from both p53-mediated and adenovirus vector-mediated mechanisms. The importance of NK cells for adenovirus-mediated tumor suppression after intratumoral dosing was demonstrated using MDA-MB-231 human breast cancer xenografts in scid (defective T and B cell response) and scid-beige (defective T, B, and NK cell response) mice. There was no adenovirus vector-mediated anti-tumor activity in scid-beige mice. Dexamethasone (Dex) is a potent suppressor of the cellular immune response to recombinant adenovirus in mice and rats. Dex abolished growth suppression caused by adenovirus vector, but did not interfere with the anti-tumor efficacy of p53. Supression of NK cell activity in scid mice using intravenous administration of a neutralizing antibody had the same effect as Dex. These data support a role for NK cells in adenovirus vector-mediated anti-tumor efficacy.
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PMID:NK cells mediate the anti-tumor effects of E1-deleted, type 5 adenovirus in a human tumor xenograft model. 1060 10

In this study the effects of SN-38 on colon adenocarcinoma cell lines expressing wild-type p53 (LS174T) or mutant non-functional p53 (HT29) have been investigated. On exposure to SN-38, HT29 cells rapidly progressed through G1 and S and arrested in G2/M. Release and concomitant increase in apoptosis after 48 h was concentration- and time-dependent (P < 0.001), being more rapid at higher concentrations, but reaching plateau at 10 ng ml(-1) with prolonged exposure. LS174T cells showed only a small increase in apoptosis, and only at high concentrations (50-100 ng ml(-1)). The main effect of SN-38 in LS174T cells was prolonged cell cycle arrest, which was independent of concentration. Arrest occurred in all phases of the cell cycle, with the distribution depending on concentration (P < 0.001) and not duration (P > 0.05). With increasing concentration, LS174T cells arrested in G2/M, S and G1. Cell cycle arrest was coincident with increased p53 expression in each phase of the cell cycle. Expression in G1 increased with time and concentration (P < 0.001, P = 0.01 respectively)whereas in S and G2/M p53 expression increased only with time (P< 0.001). Dose-dependent p53-associated G1 arrest, in the absence of DNA synthesis indicates an additional cytotoxic mechanism for SN-38, which requires higher concentrations than the S phase mechanism, and detection of which seems to involve p53. For incubations with the same ED (exposure x duration), apoptosis in HT29 cells was significantly higher for prolonged exposure to lower concentrations, whereas in LS174T cells there was a trend towards increased apoptosis with shorter exposures to higher concentrations, indicating a schedule effect of SN-38. Although expression of wild-type p53 leads to a more rapid induction of apoptosis, SN-38 cytotoxicity was generally greater in cells with mutant p53, as wild-type cells escaped apoptosis by p53 associated prolonged cell cycle arrest. Thus, pulsed schedules with higher doses may be more effective in cells expressing wild-type p53, whereas continued exposure with protracted schedules may be more active in cells expressing mutant p53.
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PMID:Schedule-dependent cytotoxicity of SN-38 in p53 wild-type and mutant colon adenocarcinoma cell lines. 1060 24

In this review we describe the multiple functions of p53 in response to DNA damage, with an emphasis on p53's role in DNA repair. We summarize data demonstrating that p53, through its various biochemical activities and via its ability to interact with components of the repair and recombination machinery, actively participates in various processes of DNA repair and DNA recombination. An important aspect in evaluating p53 functions arises from the finding that the p53 core domain harbors two mutually exclusive biochemical activities, sequence-specific DNA binding, required for its transactivation function, and 3'->5' exonuclease activity, possibly involved in various aspects of DNA repair. As modifications of p53 that lead to activation of its sequence-specific DNA-binding activity result in inactivation of its 3'-> 5' exonuclease activity, we propose that p53 exerts its functions as a 'guardian of the genome' at various levels: in its non-induced state, p53 should not be regarded as a non-functional protein, but might be actively involved in prevention and repair of endogenous DNA damage, for example via its exonuclease activity. Upon induction through exogenous DNA damage, p53 will exert its well-documented functions as a superior response element in various types of cellular stress. The dual role model for p53 in maintaining genomic integrity significantly enhances p53's possibilities as a guardian of the genome.
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PMID:Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. 1061 11

Cancer chemoprevention uses natural- or synthetic chemical compounds to reverse, suppress or to prevent one or more of the biological events leading to the development of cancer. Chemopreventive agents are classified as blocking or suppressing according to their action on either the initiation or promotion-progression phases in experimental models using carcinogen treated animals. Transgenic animal technology has resulted in a plethora of murine models for cancer research providing insight into the complex oncogenic events contributing to the loss of cell cycle control and tumourigenesis. Transgenic models also offer an important opportunity to identify and study both tumourigens and chemopreventive agents. However, so far chemoprevention has in such models only been investigated to a limited degree and primarily in models with inactivated tumour suppressor genes. Studies show that spontaneous tumour developing due to loss of p53 function may be offset by preventive measures. The preventive actions of retinoids and polyamine synthesis inhibitors have been studied in the PIM mouse susceptible to lymphoma development. Most chemopreventive studies have been performed on murine familial adenomatous polyposis (FAP) models, which carry one non-functional apc gene and develop multiple intestinal adenomas upon inactivation of the wild type allele. Particularly non-steroidal anti-inflammatory drugs NSAIDs, which block COX-2, but also food components such as n-3 fatty acids show promising chemopreventive effects in these models. Transgenic cancer models demonstrate a strong gene-environment interaction, which is promising for the development of chemopreventive strategies.
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PMID:Use of transgenic mice in identifying chemopreventive agents. 1072 Jul 73

UCN-01 is undergoing Phase I evaluation and is a candidate for combination strategies in the clinic. UCN-01 has been shown to have a variety of effects on cellular targets and the cell cycle. It has also been reported to sensitize cells to several clinical drugs in vitro, possibly in a manner related to p53 status. Thus, combinations of UCN-01 with a series of clinical agents in variety of cell lines have been investigated in vitro. Certain cell lines demonstrated synergistic interactions with combinations of UCN-01 (20-150 nM) and thiotepa, mitomycin C, cisplatin, melphalan, topotecan, gemcitabine, fludarabine or 5-fluorouracil. In contrast, UCN-01 combinations with the antimitotic agents, paclitaxel and vincristine, or topoisomerase II inhibitors, adriamycin and etoposide, did not result in synergy, only in additive toxicity. Cells with non-functional p53 were significantly more susceptible to the supra-additive effects of certain DNA-damaging agents and UCN-01 combinations, than cells expressing functional p53 activity. In contrast, there was no significant relationship between p53 status and susceptibility to synergy between antimetabolites and UCN-01. The mechanism behind the observed synergy appeared unrelated to effects on protein kinase C or abrogation of the cell cycle in G2. Moreover, increased apoptosis did not fully explain the supradditive response. These data indicate that UCN-01 sensitizes a variety of cell lines to certain DNA-damaging agents (frequently covalent DNA-binding drugs) and antimetabolites in vitro, but the mechanism underlying this interaction remains undefined.
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PMID:UCN-01 enhances the in vitro toxicity of clinical agents in human tumor cell lines. 1085 90

It was our intention to enlighten the controversy between the mainstream of studies and our previous results showing a correlation between the intrinsic radiosensitivity and the p53 allele status of 20 human head and neck squamous cell carcinoma (HNSCC) cell lines. In our study cell lines carrying a wild-type (WT) p53 allele were significantly more radioresistant than cell lines which lacked a WT gene. We observed nine HNSCC cell lines with known intrinsic radiosensitivity and p53 allele status with time-lapse video microscopy after irradiation with 2 and 3 Gy. We studied the mitotic and apoptotic frequencies and scored the apoptoses as to whether they occurred morphologically in mitosis or in interphase. Irradiation with 2 or 3 Gy did not induce apoptosis in the cell lines studied. As expected the mitotic frequency was reduced by the irradiation. This was statistically significant in the cell lines which were radiosensitive when measured with a clonogenic assay. p53 allele status did not have an independent effect on the cell lines, except that the irradiation favoured the apoptosis in mitosis in the cell lines with WT p53 and the apoptosis in the interphase in the cell lines with a mutated or non-functional p53 gene. We conclude that although the apoptosis is not induced by irradiation with 2 Gy or 3 Gy, the p53 suppressor gene seems to influence the process of apoptosis after irradiation in the cell lines studied.
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PMID:The effect of irradiation on mitotic and apoptotic frequency in head and neck cancer cell lines, the correlation to p53 mutations and clonogenic survival. 1092 63

SV40 large T antigen-induced primitive neuroectodermal tumors of the rat provide a model system to study induction and progression of primitive neuroectodermal tumors at the molecular level. A cell line derived from such a tumor reproducibly gave rise to malignant derivatives that ceased large T-antigen expression but harbored a mutant p53 allele with a common mutation at Cys(174) to Tyr (C174Y). To determine whether this p53 mutation contributes to tumor progression, we analyzed mutant C174Y functionally. Co-transfection experiments in Saos-2 cells with mutant or wild-type p53 and reporter genes linked to various p53-responsive promoters revealed that mutant C174Y failed to transcriptionally transactivate the Mdm2, Waf1, Cyclin G and Bax promoters. Loss of transcriptional activation correlated with loss of DNA-binding activity. Moreover, mutant C174Y exhibited a dominant negative effect on co-expressed wild-type p53. The ability of mutant p53 to repress the viral RSV, LTR or SV40 early promoters or the cellular fos promoter was likewise impaired. In contrast, it showed even induction of the fos promoter. Consistent with these observations, mutant C174Y was non-functional in the suppression of Saos-2 cell growth and even conferred a growth advantage to the cells. Surprisingly, mutant C174Y was also impaired in nuclear transport, as revealed by immunofluorescence analyses. Taken together, our results demonstrate that mutant C174Y possesses features that can positively contribute to cancer progression.
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PMID:Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation. 1100 63

The 26S proteasome is a non-lysosomal multicatalytic protease complex for degrading intracellular proteins by ATP/ubiquitin-dependent proteolysis. Tightly ordered proteasomal degradation of proteins critical for cell cycle control implies a role of the proteasome in maintaining cell proliferation and cell survival. In this study, we demonstrate that cell-permeable proteasome inhibitors, lactacystin, benzyloxycarbonyl(Z)-leucyl-leucyl-leucinal (ZLLLal; MG-132) and 4-hydroxy-5-iodo-3-nitrophenylacetyl-leucyl-leucyl-leucine vinyl sulfone (NLVS), induce apoptosis abundantly in p53-defective leukemic cell lines CCRF-CEM, U937 and K562 as well as in myelogenic and lymphatic leukemic cells obtained from adult individuals with relapsed acute leukemias. Leukemic cell apoptosis induced by the proteasome inhibitors was dependent on activation of caspase-3 and related caspase family proteases, because caspase-3 inhibitor N-acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspartal (Ac-DEVD-cho) and, more effectively, the general caspase-inhibitor N-benzyloxycarbonyl-L-valyl-L-alanyl-L-aspartate fluoromethylketone (Z-VAD-fmk) were capable of blocking apoptosis induced by lactacystin, ZLLLal or NLVS. Induction of apoptosis by lactacystin or ZLLLal was accompanied by cell cycle arrest at G2/M phase and by accumulation and stabilization of cyclin-dependent kinase inhibitor p21WAF1/Cip and tumor suppressor protein p53. A role of p53 in mediating apoptosis or induction of p21WAF1/Cip1 was ruled out since CCRF-CEM and U937 cells express non-functional mutant p53, and K562 cells lack expression of p53. Viability and hematopoietic outgrowth of human CD34+ progenitor cells treated with lactacystin were slightly reduced, whereas treatment of CD34 + cells with ZLLLal or the cytostatic drugs doxorubicin and gemcitabine resulted in markedly reduced viability and hematopoietic outgrowth. These results demonstrate a basic role of the proteasome in maintaining survival of human leukemic cells, and may define cell-permeable proteasome inhibitors as potently anti-leukemic agents which exhibit a moderate hematopoietic toxicity in vitro.
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PMID:Proteasome inhibitors induced caspase-dependent apoptosis and accumulation of p21WAF1/Cip1 in human immature leukemic cells. 1107 63


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