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)

Drug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which confers cross-resistance to hydrophobic natural product cytotoxic drugs. Expression of the MDR1 gene can occur de novo in human cancers in the absence of drug treatment. The promoter of the human MDR1 gene was shown to be a target for the c-Ha-Ras-1 oncogene and the p53 tumor suppressor gene products, both of which are associated with tumor progression. The stimulatory effect of c-Ha-Ras-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. These results imply that the MDR1 gene could be activated during tumor progression associated with mutations in Ras and p53.
 ...
PMID:Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. 134 76

Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.
 ...
PMID:[How do cancers resist to chemotherapy?]. 136 90

Overexpression of the MDR1 product, P-glycoprotein (Pgp), has been shown to be one of the mechanisms underlying the development of multidrug resistance (MDR). Recently, one mutant p53 has been shown to stimulate the MDR1 gene promoter in vitro, whereas wild-type p53 repressed this activity. We measured Pgp and p53 expression by immunoblotting in 34 colorectal tumours, and performed mutation analyses on the p53-positive tumours to confirm the presence of mutant p53 protein. Tumour DNA indices (DIs) were also measured using flow cytometry. Pgp was detected in 44% (15/34) of the tumours and in 100% (13/13) of the normal mucosas (P = 0.0005), with highest levels of expression seen in normal mucosa, suggesting that initial drug resistance in colorectal tumours is not caused by Pgp. Highly DNA aneuploid tumours demonstrated the lowest levels of Pgp expression relative to moderately aneuploid and diploid colorectal tumours. p53 protein was detected in 53% (18/34) of the tumours, and 12 of 14 p53-positive tumours had p53 gene mutations, p53-negative tumours had approximately twice the level of Pgp expression of p53-positive tumours. Pgp expression was not associated with either p53 expression (P = 0.73) or incidence of p53 gene mutation (P = 0.70), suggesting that mutant p53 does not induce Pgp overexpression in colorectal carcinomas.
 ...
PMID:P-glycoprotein is not expressed in a majority of colorectal carcinomas and is not regulated by mutant p53 in vivo. 764 Feb 10

Two new myeloid cell lines (K051 and K052) were established from a patient with multilineage CD7-positive acute leukemia. The K051 and K052 were established from the patient's bone marrow cells at diagnosis and at relapse, respectively. The K051 cell expressed myeloid-associated antigens (CD13 and CD33), a platelet-associated antigen (CD41), and an erythroid antigen (glycophorin A). The K052 cell expressed myeloid-associated antigens (CD13, CD14, and CD33), lymphoid markers (CD2, CD5, and CD7), and HLA-DR. Chromosome analysis of both cell lines showed a 17p- chromosome. Both cell lines were investigated for aberrations of the p53 gene and the N-ras gene. A p53 mutation detected in both cell lines consisted of a C-->T substitution in codon 248. An N-ras mutation detected only in the K052 cell consisted of a G-->C substitution in codon 13. Expression of the multidrug resistance gene (MDR1) was also investigated by the semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). MDR1-mRNA was more highly expressed by the K052 cell than the K051 cell, being equivalent to that in HEL cells. The functional MDR1-protein against vincristine was also observed, and its function was inhibited by verapamile and Cyclosporin A. The K052 cells were capable of phenotypic or morphologic differentiation after being incubated with granulocyte colony-stimulating factor, interleukin-2, phorbol 12-myristate 13-acetate, or 1,25-dihydroxy-vitamin D3. In contrast, the K051 cells responded phenotypically to retinoic acid. Thus, the K051 and K052 cell lines will be useful for investigating the cellular and molecular events in leukemogenesis and differentiation, and the mechanism of expression of the MDR1 gene.
 ...
PMID:p53 and N-ras mutations in two new leukemia cell lines established from a patient with multilineage CD7-positive acute leukemia. 769 50

Our knowledge of the molecular biology of sarcomas has progressed considerably over the past year, with major emphasis on the role of p53 and MDM2 gene mutations. Further studies on drug resistance mechanisms and the role of MDR1 expression in sarcomas have been reported. The investigations using different imaging techniques as ways of predicting tumor necrosis more accurately than our current response measurements after therapy have led to promising results. The many clinical phase II studies with new drugs led to the identification of taxotere as a new active agent against soft tissue sarcomas. Similar impressive results, such as those obtained with isolated limb perfusion in melanoma, have been reported in limb sarcomas with an identical regimen. The activity of ifosfamide in pretreated patients, administered at an increased dose, is suggestive of dose dependency. The improved results in phase II studies of dose-intensive chemotherapy with the support of colony-stimulating factors are encouraging and these regimens are now being investigated in the adjuvant setting.
 ...
PMID:Diagnosis and treatment of soft tissue sarcomas in adults. 780 38

The effect of human wild type and mutant p53 proteins on the human multidrug resistance (MDR1) promoter was studied in a p53-negative human cell line. Transient expression of MDR1 promoter-chloramphenicol acetyltransferase reporter gene constructs (MDRCAT) cotransfected with p53 expression vectors was analyzed in H358 lung carcinoma cells. Cotransfection with a wild type p53 expression vector stimulated MDRCAT activity, while cotransfection with mutant p53 expression vectors altered at amino acid positions 181, 252, 258, or 273 failed to stimulate expression. Wild type p53 stimulation of MDRCAT activity was time dependent with maximal expression occurring 24-30 h following transfection and correlating with high p53 protein levels. MDR1 promoter deletion analysis suggested that the sequences involved in wild type p53 stimulation of MDRCAT activity were contained within the region from -39 to +53 relative to the start of transcription at +1. This region contains no TATA or p53 consensus binding sequence but does contain an initiator sequence. Wild type p53 stimulation of MDRCAT expression also occurred in parental and doxorubicin-resistant SW620 colon and parental 2780 ovarian cancer cell lines, indicating that wild type p53-mediated simulation of the MDR1 promoter is not restricted to a single cell line.
 ...
PMID:Wild type p53 stimulates expression from the human multidrug resistance promoter in a p53-negative cell line. 782 27

In order to assess the clinical role of the MDR1 gene in chronic lymphocytic leukemia (CLL), we determined its expression in the leukemic cells of 39 patients with CLL and compared this with other clinical and laboratory parameters. MDR1 RNA expression was detected in 29 patients. MDR1 RNA transcripts were independent of age, treatment status of the patients and the clinical stage of CLL, but correlated with the white blood cell count and MDR2 RNA transcripts. Expression of the tumor suppressor gene p53 was found in 30 out of 37 patients and was associated with MDR1 RNA expression (P < 0.001). Immunocytochemistry using the monoclonal antibody C219 was performed in 38 patients, and in 28 cases, more than 5% of the leukemic cells were found to express cell surface P-glycoprotein. P-glycoprotein expression correlated with the expression of MDR1 RNA (P = 0.048).
 ...
PMID:MDR1 gene expression in chronic lymphocytic leukemia. 791 28

Multidrug resistance in human cancer is associated with overexpression of the MDR1 gene, which encodes a plasma membrane energy-dependent efflux pump termed P-glycoprotein (or the multidrug transporter), which confers cross-resistance to multiple hydrophobic natural product cytotoxic drugs. We have previously shown in cotransfection experiments that activity of the human MDR1 gene promoter is modulated by Ras and p53, suggesting that expression of the MDR1 gene may be associated with the activation of oncogenes and/or functional loss of tumor suppressor genes during oncogenesis. To further characterize the effects of p53 on the MDR1 promoter, we have shown in the current study that the region of the promoter that is required for transactivation by p53 mutants overlaps with the region that is essential for basal promoter activity. In addition, we also have shown that several different p53 mutants transactivate the MDR1 promoter in several different cell types, including embryo fibroblasts derived from the p53-deficient (p53-l-) mice generated by gene targeting.
 ...
PMID:Transactivation of the human multidrug resistance (MDR1) gene promoter by p53 mutants. 794 67

We studied 53 patients with B-cell chronic lymphocytic leukemia (B-CLL) and found mutations of the p53 gene in 15%. Patients with p53 gene mutations were found to have an aggressive form of B-CLL disease characterized by advanced Rai stage, rapid lymphocyte doubling time (LDT), and resistance to chemotherapy. While 27 of 29 treated patients (93%) without p53 mutations achieved a partial remission, only one of seven treated patients (14%) with p53 mutations achieved a partial remission (P = .00009). Adjusting for prognostic factors (age, sex, race, and Rai stage), patients with p53 gene mutations had a 13-fold greater risk of death than patients without p53 mutations (P = .013). In addition to examining the clinical relevance of p53 gene mutations in B-CLL, we investigated the possible role of p53 gene regulation in the expression of the multidrug resistance genes MDR1 and MDR3. We quantitated MDR1 and MDR3 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Expression of both the MDR1 and MDR3 genes was independent of p53 gene mutation or prior drug treatment, and did not predict for clinical response. Our findings indicate that p53 gene mutations in B-CLL are associated with a poor clinical outcome and may be a prognostic indicator for drug resistance.
 ...
PMID:p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. 824 11

Genetic and molecular abnormalities, in association with malignant phenotypes, have been previously demonstrated in a variety of human tumors. Although the multistep theory fits well for some cancers such as retinoblastoma and colon carcinoma, for many others it still remains to be proven. Neuroblastoma, a tumor found in pediatric patients, seems to fall into the multistep model. Nonrandom chromosome abnormalities have been found with 1p deletion, loss of heterozygosity for short arm of chromosome 1 and for chromosome 11q and 14q. Amplification of N-myc oncogene and an increased level of Ras protein have also been demonstrated. Therefore, even if it is not possible to show that these mutations happen as discrete events in their order of appearance, the multistep model seems involved in neuroblastoma development. Neuroblastoma has a peculiar aspect, however, that makes this tumor a natural model of defect of cell differentiation. In fact, there is a particular subset of metastatic tumors that show spontaneous regression. In vitro, neuroblastoma cell lines can be induced to differentiate along the neural pathway using retinoic acid. Other natural and chemical substances are also able to induce cell differentiation. During retinoic acid treatment, N-myc oncogene expression decreases and other genes are deregulated. p53 and MDR1 gene expression increases. These two different aspects, failure of cell differentiation pathway and genetic mutations, make the neuroblastoma one of the most difficult problems of modern molecular biology.
 ...
PMID:Neuroblastoma: the result of multistep transformation? 840 Dec 51


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