Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse embryo fibroblasts lacking poly(ADP-ribose) polymerase (PARP)-1 express a barely detectable level of wild-type (wt) p53 protein. Doxorubicin at concentrations activating wt p53 in normal mouse embryo fibroblasts failed to induce it in mutant cells. wt p53 was only activated in response to a 10-fold higher doxorubicin dose. Treatment with higher doxorubicin concentrations was cytotoxic for normal but not for PARP-1 -/- cells. The latter was also resistant to other anticancer agents. The increased resistance of mutant cells to drugs resembled a unique phenomenon known as multidrug resistance (MDR). Interestingly, the MDR gene product P-glycoprotein was clearly up-regulated in PARP-1-deficient cells as compared with normal counterparts. Pretreatment with verapamil reversed the MDR phenotype.
 ...
PMID:Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein. 1094 36

The tumor suppressor protein p53 is a sequence-specific DNA-binding protein, and its biological responses are very often mediated by transcriptional activation of various target genes. Here we show that caspase-1 (interleukin-1beta converting enzyme), which plays a role in the production of proinflammatory cytokines and in apoptosis, is a transcriptional target of p53. Caspase-1 mRNA levels increased upon overexpression of p53 by transfection in MCF-7 cells. Human caspase-1 promoter showed a sequence homologous to the consensus p53-binding site. This sequence bound to p53 in gel shift assays. A caspase-1 promoter-reporter construct was activated 6-8-fold by cotransfection with normal p53 but not by mutant p53 (His(273)) in HeLa, as well as MCF-7, cells. Mutation of the p53-binding site in caspase-1 promoter abolished transactivation by p53. Treatment of p53-positive MCF-7 cells with the DNA-damaging drug, doxorubicin, which increases p53 levels, enhanced caspase-1 promoter activity 4-5-fold, but similar treatment of MCF-7-mp53 (a clone of MCF-7 cells expressing mutant p53) and p53-negative HeLa cells with doxorubicin did not increase caspase-1 promoter activity. Doxorubicin treatment increased caspase-1 mRNA levels in MCF-7 cells but not in MCF-7-mp53 or HeLa cells. These results show that endogenous p53 can regulate caspase-1 gene expression.
 ...
PMID:Direct transcriptional activation of human caspase-1 by tumor suppressor p53. 1127 53

To determine whether the expression of p53, p21, bcl-2 or Ki-67 in cancer cells is predictive of chemosensitivity, immunohistochemical examination of these factors and chemosensitivity assays were performed on colon and gastric cancer specimens. Chemosensitivity tests were performed using CDDP, 5-FU, MMC, or ADR and inhibition rate (IR) was calculated by MTT assay. Before exposure to anticancer drugs, the samples were investigated immunohistochemically for expression of the above factors and after anticancer drug exposure by TUNNEL staining, for the presence of apoptotic cells. With 5-FU and MMC, the apoptotic index was well correlated with IR, so their effects were related to apoptosis. Moreover, with these two agents, the p53 labeling index (LI) was inversely correlated with IR and p21-LI showed a good correlation with IR. We therefore concluded that immunohistochemical studies for p53 and p21 were useful for predicting the chemosensitivities of colon and gastric cancer to MMC and 5-FU.
 ...
PMID:Correlation of immunohistochemical p53 labeling index with inhibition rate in chemosensitivity test in gastric and colon cancer. 1129 39

We investigated endocytosis activity, uptake of miltefosine (hexadecylphosphocholine), phospholipid and cholesterol content, the cell cycle, and apoptosis in 13 tumor cell lines (MCF7, MCF7/ADR, KB-3-1, KB-8-5, KB-C1, HeLa, HeLa-MDR1-G185, HeLa-MDR1-V185, CCRF/CEM, CCRF/VCR1000, CCRF/ADR5000, HL-60, HL-60/AR) with different sensitivities to treatment with the antitumor phospholipid analogues miltefosine and D-21266 (octadecyl-(N,N-dimethyl-piperidino-4-yl)-phosphate). In this panel of cell lines, MDR1 (multidrug resistance gene 1)- and MRP1 (multidrug resistance-associated protein)-expressing cells were found to be slightly more resistant to both compounds than sensitive parental cells. No correlation was found between resistance to miltefosine and endocytosis, intracellular concentration of miltefosine, the phospholipid and cholesterol content, induction of apoptosis, or cell cycle alterations in all the cell lines tested. Wild-type p53 containing WMN Burkitt's lymphoma cells and wild type p53-deficient CA46 exhibited similar sensitivities to miltefosine. The low percentage of apoptosis induced in MCF7 cells lacking caspase 3 indicated that caspase 3 seems to play an essential role in miltefosine-induced apoptosis.
 ...
PMID:Effects of miltefosine on various biochemical parameters in a panel of tumor cell lines with different sensitivities. 1155 22

Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53(+/-) mutation significantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ERalpha and p16 negative. Translocations involving p53 were also identified which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or gamma-irradiation, suggesting that these methods would be effective in treatment of this disease.
 ...
PMID:Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. 1170 23

The p53 tumor suppressor gene is the most frequently mutated gene in human cancers, and germ-line p53 mutations cause a familial predisposition for cancer. Germ-line or sporadic p53 mutations are usually missense and typically affect the central DNA-binding domain of the protein. Because p53 functions as a tetrameric transcription factor, mutant p53 is thought to inhibit the function of wild-type p53 protein. Here, we studied the possible dominant-negative inhibition of wild-type p53 protein by two different, frequently occurring point mutations. The R270H and P275S mutations were targeted into the genome of mouse embryonic stem cells to allow the analysis of the effects of the mutant proteins expressed in normal cells at single-copy levels. In embryonic stem cells, the presence of a heterozygous point-mutated allele resulted in delayed transcriptional activation of several p53 downstream target genes on exposure to gamma irradiation. Doxorubicin-induced apoptosis was severely affected in the mutant embryonic stem cells compared with wild-type cells. Heterozygous mutant thymocytes had a severe defect in p53-dependent apoptotic pathways after treatment with gamma irradiation or doxorubicin, whereas p53-independent apoptotic pathways were intact. Together these data demonstrate that physiological expression of point-mutated p53 can strongly limit overall cellular p53 function, supporting the dominant-negative action of such mutants. Also, cells heterozygous for such mutations may be compromised in terms of tumor suppression and response to chemotherapeutic agents.
 ...
PMID:Targeted point mutations of p53 lead to dominant-negative inhibition of wild-type p53 function. 1186 59

The relationship between p53 gene status and the expression of DR5 and Fas was evaluated as a function of sensitivity of 11 acute lymphoblastic leukemia cell lines to adriamycin, etoposide, vincristine, methotrexate and dexamethasone. There was up to a 37-fold increase in expression of DR5 following treatment with ADR or VP-16 only in cells with wt p53. A direct correlation was observed between enhanced DR5 expression and sensitivity to ADR and VP-16. There was no induction of DR5 following treatment with VCR, MTX or DEX. There was up to a 51-fold increase in the median level of expression of Fas following treatment with ADR and VP-16, and unlike DR5 this occurred in cells with either wild-type or mutant p53. Nevertheless, a direct correlation was observed between Fas expression and drug-sensitivity. Conversely, there was only a two-fold increase in expression of Fas after exposure to VCR, MTX and DEX. These findings suggest that DR5 mediates sensitivity to ADR and VP-16 in a p53-dependent manner, whereas, Fas appears to mediate sensitivity to these two drugs independent of p53 status. DR5 and Fas do not appear to play a major role as determinants of chemosensitivity to VCR, MTX and DEX.
 ...
PMID:Comparison of DR5 and Fas expression levels relative to the chemosensitivity of acute lymphoblastic leukemia cell lines. 1191 27

Internalization and subcellular fate of free doxorubicin or its polymeric conjugates based on poly N-(2-hydroxypropyl)methacrylamide (pHPMA), either non-targeted or targeted with anti-Thy1.2 or anti-CD71 monoclonal antibody was tested on EL-4 mouse T-cell lymphoma, SW620 human colorectal carcinoma and OVCAR-3 human ovarian adenocarcinoma. Doxorubicin fluorescence allowed us to follow the internalization and intracellular distribution of tested conjugates by laser scanning confocal microscopy and/or by fluorescent microscopy. Whereas free doxorubicin was always detectable only in the nuclei of treated cells, detectable fluorescence of doxorubicin bound to a polymeric carrier, targeted or non-targeted, was detectable up to 3 days of incubation only in the cytoplasmatic structures. While free doxorubicin causes apoptosis in the populations of tested cancer cell lines, significant number of apoptotic cells was never found in cell cultures exposed to targeted or non-targeted polymeric conjugates. In contrast to free doxorubicin, which is a strong inducer of p53 expression, increased p53 expression was never observed after the treatment with the polymeric drug. High-performance liquid chromatographic analysis shows that the percentage of cleaved doxorubicin is very low even after 48 h of incubation of tested cells with the polymeric conjugate, and cannot be the only reason for the toxicity of the conjugate. We suggest that: (a) after the treatment with pHPMA-bound drug, the cells die by necrosis and (b) the toxicity of pHPMA-based conjugates is a combination of the toxic effect of released doxorubicin and the toxic effect of doxorubicin in polymer-bound form directed against cell membranes.
 ...
PMID:Differences in the intracellular fate of free and polymer-bound doxorubicin. 1194 91

LCC2, an estradiol-independent tamoxifen (Tax)-resistant subline of MCF-7 human breast cancer cell line, is resistant relatively towards Tax and methotrexate (Mtx). The purpose of the present study is to evaluate the role of p53 in determining this resistance. While MCF-7 is sensitive to and undergoes apoptosis, as determined by propidium iodide stain, by Tax and Mtx, LCC2 is resistant to apoptosis induction by these agents. Both cell lines undergo apoptosis and are sensitive equally to doxorubicin (Adr). p53 cDNA of both sublines was evaluated by polymerase chain reaction (PCR) amplification and sequencing and was found to be of wild-type. p53 mRNA, as well as protein, are elevated markedly in LCC2 as compared to MCF-7 cells. p53 expression was increased by estradiol and Adr, not changed by Mtx, and decreased by Tax and estradiol-deprivation in both sublines. p53 modulation by the various agents, in both sublines, was evaluated by cytochemical staining and subcellular fractionation. This analysis showed that p53 is localized mainly in the nuclear fraction in MCF-7 cells, and in the cytoplasmatic fraction in LCC2 cells. Doxorubicin induced apoptosis in MCF-7 cells along with increase in its nuclear fraction. In contrast, LCC2 underwent apoptosis by Adr despite its cytoplasmatic sequestration. These experiments demonstrate that p53 is sequestered to cytoplasm in the estrogen-independent, Tax-resistant LCC2 cells. However, the differences in apoptotic rate between MCF-7 and LCC2 cells do not seem to be dependent on p53. The LCC2 cell line may serve as a useful model for the study of the mechanism of cytoplasmatic sequestration of wild type (wt) p53, its physiologic consequences, and its relation to estrogen-independence or Tax resistance of breast cancer cells.
 ...
PMID:Altered subcellular localization of p53 in estrogen-dependent and estrogen-independent breast cancer cells. 1209 46

Current therapy for advanced prostate cancer is largely based on androgen deprivation and is mostly palliative because all patients eventually relapse with androgen-independent disease. Doxorubicin (Dx), an anthracycline used commonly as a chemotherapeutic agent in relapsed prostate cancer, is a strong inducer of p53 expression and p21(CIP1/WAF1) (p21) transactivation. Previous reports suggest that p21 may have a role in the modulation to chemotherapy-induced apoptosis, prostate cancer progression and androgen regulation. In order to investigate if p21 has a pro-survival role in the response of prostate cancer cells to cellular stress, we exposed two androgen-regulated human prostate cancer cell lines (MDA PCa 2b and LNCaP) to Dx and growth factor withdrawal. We then studied expression of p53 and p21, cell-cycle kinetics and apoptosis. We have found that p53 protein accumulated in a dose- and time-dependent manner after Dx treatment, while p21 expression increased over time with low but decreased with high Dx doses. Apoptosis occurred in parallel with p21 down-modulation. Dx treatment of p53 knockout cells demonstrated that p21 induction was strictly p53 dependent. Reduction of p21 levels in prostate cancer cells with an antisense p21 adenovirus resulted in sensitization to Dx and accelerated onset of apoptosis in response to growth factor withdrawal. The evidence presented here also suggests that caspase activation mediates the apoptosis in this system and supports that p21 may modulate the threshold of apoptosis in prostate cancer. These observations may thus provide implications onto the integration of chemotherapy and androgen ablation.
 ...
PMID:p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells. 1215 46


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