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)

Recent classifications of non-Hodgkin's lymphomas (NHL) have strictly individualized mantle cell lymphoma (MCL) on the basis of a combination of morphologic, immunophenotypic, and cytogenetic criteria. This clinicopathological entity now appears to be a biological and therapeutic model for the understanding and treatment of hematologic malignancies. The lymphomogenesis of MCL could be explained by a series of genetic abnormalities which occur at different steps of the disease: (1) mutation and/or loss of the ATM gene in centrocytic cells of the follicle mantle of lymph nodes, leading to the loss of ATM function, particularly involved during the V(D)J recombination process; (2) a t(11;14)(q13;q32) translocation which induces a constitutive Bcl-1/PRAD1/CCND1 expression, responsible for cell cycle activation of centrocytic cells characteristic of typical MCL; and (3) secondary additional chromosomal aberrations, such as a p53 mutation, observed in blastic transformation of MCL. Despite the evaluation of a number of treatment modalities, the optimal management of MCL has not yet been defined: (1) conventional and intensified chemotherapy and monoclonal anti-CD20 antibody therapy appear to be effective for the improvement of response rates and event-free or overall survivals; (2) combinations of different treatment modalities must be tested to modify the natural dismal outcome of the disease; and (3) innovative approaches should be developed. From this point of view, all these considerations offer a fine opportunity for extensive medical reflection.
 ...
PMID:Mantle cell lymphoma: a biological and therapeutic paradigm. 1215 64

Leukemia, a form of haematological malignancy, is a multi-stage disease and a wide range of diverse genes has been speculated to correlate with its initiation and development. Ras has been speculated to be an initiating gene for haematological malignancy, but more investigation will be needed to determine the genes associated with the progression of the disease. 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat leukemia provides a good tool for research into various stages of the disease. The entire coding regions of p53 and ras genes were examined for mutations in the present study. In this experiment, we used fluorescence-labeled polymerase chain reaction single-stranded conformation polymorphism analysis (PCR-SSCP) and direct sequencing to detect mutations of both genes on rat erythroleukemia. Fifteen out of 18 (83.3%) rat leukemias were found to have N-ras codon 61 mutation, consistent with previous results. The result of direct sequencing showed a single base substitution (CAA to CTA), resulting in an amino-acid change from Gln to Leu. No mutations were found in H-ras, K-ras or codon 12 of N-ras. The incidence of p53 gene mutation was 16.6% (3/18) in rat leukemia at late-stage. In the present study, mutation of the p53 gene was detected in three DMBA-induced leukemias as follows: a single-base substitution (CAT to CGT) at codon 177 (exon 5), resulting in an amino-acid change from Arg to Leu, a CGG to CTG/CGG changed at codon 211 (exon 6) resulting in an amino-acid change from His to Arg/His, and a GGG to TGG at codon 242 (exon 6) resulting in an amino-acid change from Gly to Trp, respectively. Thus, mutations of p53 gene do not seem to respond to the carcinogenesis of the DMBA-induced leukemia, in contrast to mutation of the N-ras oncogene, and may possibly be involved in the progress of multi-stage leukemogenesis.
 ...
PMID:Incidence of p53 and ras gene mutations in DMBA-induced rat leukemias. 1238 83

Although B-cell chronic lymphocytic leukemia (B-CLL) is the most common form of leukemia in Western countries, little is known about its underlying molecular abnormalities and their prognostic significance, particularly for use in early therapeutic interventions in young patients. As TP53 tumor suppressor gene abnormalities and 11q23 deletions are reported to be prognostically adverse in hematologic malignancies, we used interphase fluorescence in situ hybridization to analyze their incidence and prognostic significance in young B-CLL patients. Bone marrow samples from 40 untreated B-CLL patients at diagnosis were studied using five yeast artificial chromosome clones from the 11q23.1 approximately q23.3 chromosomal region and a probe specific for the 17p13.1 locus. Twenty-three patients (58%) carried 11q deletions. Interestingly, 16 of 17 patients (94%) who showed early disease progression exhibited this chromosomal abnormality, suggesting that 11q deletions may help to identify more aggressive disease in early stage patients. In contrast, monoallelic TP53 deletions were found in all of the patients. The TP53 and 11q deletions were only present in a proportion of the clonal B-cells, which suggests that they are secondary events in B-CLL.
 ...
PMID:Interphase fluorescence in situ hybridization analysis of del(11)(q23) and del(17)(p13) in chronic lymphocytic leukemia. a study of 40 early-onset patients. 1255 Jul 55

We hypothesize that coordination between the two DNA parental sets in somatic cells is essential for the stability of the diploid genome, and that its disruption is associated with the many alterations observed in the various cancerous phenotypes. As coordination between two allelic counterparts is well exemplified by synchrony in replication timing, we examined, in blood cells of patients suffering from various hematologic malignancies, replication patterns of five loci. These loci were three cancer-implicated genes (TP53, AML1, and RB1) and two nontranscribed sequences engaged in chromosome segregation. All five loci normally display synchrony in allelic replication timing. In addition, in order to exemplify an asynchronous mode of allelic replication, we followed the replication of allelic counterparts of an imprinted gene (SNRPN), which is distinguished by its asynchronous mode of allelic replication (allele-specific replication). Allelic replication patterns were studied by fluorescence in situ hybridization (FISH), which has been shown to distinguish between nonreplicated and replicated regions of the genome in interphase cells, based on the structure of the specific hybridization signals that are being detected. Using the FISH replication assay we observed, for all loci which normally exhibit synchrony in allelic replication, loss of synchrony when present in blood cells of patients with hematologic malignancies. The loss of synchrony in allelic replication in patients' cells was accompanied by aneuploidy (chromosome losses and gains), the hallmark of cancer. We were able to reinstate the normal pattern of replication in the patients' cells by introducing an inhibitor of DNA methylation. It thus appears loss of allelic coordination is an epigenetic alteration characterizing cancer, which is easily identified by simple cytogenetic means and has a potential use in both cancer investigation and detection.
 ...
PMID:Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies. 1255 Jul 68

To characterize cancer risk in heterozygous p53 mutation carriers, we analyzed cancer incidence in 56 germline p53 mutation carriers and 3,201 noncarriers from 107 kindreds ascertained through patients with childhood soft-tissue sarcoma who were treated at the University of Texas M. D. Anderson Cancer Center. We systematically followed members in these kindreds for cancer incidence for >20 years and evaluated their p53 gene status. We found seven kindreds with germline p53 mutations that include both missense and truncation mutation types. Kaplan-Meier analysis showed similar cancer risks between 21 missense and 35 truncation p53 mutation carriers (log-rank chi(2)=0.04; P=.84). We found a significantly higher cancer risk in female carriers than in male carriers (log-rank chi(2)=12.1; P<.001), a difference not explained by an excess of sex-specific cancer. The calculated standardized incidence ratio (SIR) showed that mutation carriers had a risk for all types of cancer that was much higher than that for the general population (SIR = 41.1; 95% confidence interval [CI] 29.9-55.0) whereas noncarriers had a risk for all types of cancer that was similar to that in the general population (SIR = 0.9; 95% CI 0.8-1.0). The calculated SIRs showed a >100-fold higher risk of sarcoma, female breast cancer, and hematologic malignancies for the p53 mutation carriers and agreed with the findings of an earlier segregation analysis based on the same cohort. These results quantitatively illustrated the spectrum of cancer risk in germline p53 mutation carriers and will provide valuable reference for the evaluation and treatment of patients with cancer.
 ...
PMID:Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. 1261 Jul 79

It is thought that when tumor cells are treated with anticancer drugs, they die through the apoptotic pathway and that cell resistance to cancer chemotherapy is mainly a resistance to apoptosis commitment. p53 is not functional in nearly half of the tumors examined and because of its involvement (directly or through its target genes) in the apoptotic pathway, drug resistance to chemotherapy has been largely attributed to the status of this "tumor suppressor protein". Topoisomerase II (topo II) inhibitors are widely used not only as single agents, but also in the majority of combination treatment protocols for hematologic malignancies and solid tumors. The relationship between p53 and topo II raises many questions about basic regulatory, biochemical, structural and functional characteristics that could be different in cells in different tissues, and most importantly, between different tumor cell types and their normal tissue counterpart. Understanding these relationships may lead to strategies for chemotherapy optimization and further precision targeting of tumor cells in order to avoid drug resistance and thereby chemotherapy failure.
 ...
PMID:Tumor p53 status and response to topoisomerase II inhibitors. 1265 85

Resistance to Fas-mediated apoptosis (FMA) has been implicated in the pathogenesis of hematologic malignancies. Recently, a collaborative study showed that germline Fas mutations represent a genetic risk factor for the development of Hodgkin's and non-Hodgkin lymphoma. Here, we report that transformed B cell lines from familial lymphoma patients show a range of sensitivity to Fas-mediated apoptosis with lymphocytes from two patients with a marked resistance to Fas-, but not p53-mediated cell death. Fas resistance in these cells was associated with reduced recruitment of the initiator caspase 8 compared to cFlip, an inhibitor of apoptosis, to the death-inducing signaling complex (DISC). A decreased ratio of caspase 8 to cFlip in total cell extracts as well as in the DISC was associated with a profound disturbance of the Fas signaling cascade. We propose here that the relative reduction in caspase 8 to cFlip in the Fas DISC confers a survival advantage to lymphocytes and predisposes to the development of malignancy in some familial lymphoma patients.
 ...
PMID:Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients. 1280 43

Cytosine arabinoside (ara-C) is a nucleoside analog used in the treatment of hematologic malignancies. One of the major side effects of ara-C chemotherapy is neurotoxicity. In this study, we have further characterized the cell death induced by ara-C in sympathetic neurons. Similar to neurons undergoing trophic factor deprivation-induced apoptosis, ara-C-exposed neurons became hypometabolic before death and upregulated c-myb, c-fos, and Bim. Bax deletion delayed, but did not prevent, ara-C toxicity. Neurons died by apoptosis, indicated by the release of mitochondrial cytochrome-c and caspase-3 activation. p53-deficient neurons demonstrated decreased sensitivity to ara-C, but neither p53 nor multiple p53-regulated genes were induced. Mature neurons showed increased ara-C resistance. These results demonstrate that molecular mechanisms underlying ara-C-induced death are similar to those responsible for trophic factor deprivation-induced apoptosis. However, substantial differences in neuronal death after these two distinct stress stimuli exist since ara-C toxicity, unlike the developmental death, can proceed in the absence of Bax.
 ...
PMID:Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons. 1293 79

Arsenic trioxide (ATO) induces differentiation and apoptosis of malignant cells in vitro and in vivo and has been used in the treatment of a variety of hematologic malignancies. We found that in NB4 acute promyelocytic and in K562 erythroleukemia cell lines treatment with the MEK1 inhibitors PD98059 and PD184352 greatly enhances apoptotic cell death induced by ATO alone. Combined treatment results in the induction of the p53AIP1 (p53-regulated apoptosis-inducing protein 1) gene in both cell lines. Because NB4 and K562 cell lines carry an inactive p53, we investigated the possible role of p73, a p53 paralogue that has been shown to regulate several p53 target genes including p21, Bax, and p53AIP1. We found that MEK1 inhibitors reduce the levels of dominant-negative (DeltaN) p73 proteins and promote the accumulation of endogenous p73alpha through its transcriptional activation and its tyrosine phosphorylation, resulting in p21 up-regulation and significant inhibition of cell growth. ATO reduces DeltaNp73 levels and promotes a p300-mediated acetylation of endogenous p73, thus favoring cell cycle arrest and apoptosis. Finally, the combined treatment with MEK1 inhibitors and ATO enhances the affinity of phosphoacetylated p73 for the p53AIP1 promoter in vivo, as determined by chromatin immunoprecipitation experiments, leading to p53AIP1 up-regulation and increased apoptosis.
 ...
PMID:Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells. 1503 Dec 5

The MDM2 oncogene is overexpressed in many human cancers, including sarcomas, certain hematologic malignancies, and breast, colon and prostate cancers. The p53-MDM2 interaction pathway has been suggested as a novel target for cancer therapy. To that end, several strategies have been explored, including the use of small polypeptides targeted to the MDM2-p53 binding domain, anti-MDM2 antisense oligonucleotides, and natural agents. Different generations of anti-human-MDM2 oligonucleotides have been tested in in vitro and in vivo human cancer models, revealing specific inhibition of MDM2 expression and significant antitumor activity. Use of antisense oligos potentiated the effects of growth inhibition, p53 activation and p21 induction by several chemotherapeutic agents. Increased therapeutic effectiveness of chemotherapeutic drugs in human cancer cell lines carrying p53 mutations or deletions have shown the ability of MDM2 inhibitors to act as chemosensitizers in various types of tumors through both p53-dependent and p53-independent mechanisms. Inhibiting MDM2 appears to also have a role in radiation therapy for human cancer, regardless of p53 status, providing a rationale for the development of a new class of radiosensitizers. Moreover, MDM2 antisense oligonucleotides potentiate the effect of epidermal growth factor receptor (EGFR) inhibitors by affecting in vitro and in vivo proliferation, apoptosis and protein expression in hormone-refractory and hormone-dependent human prostate cancer cells. These data support the development, among other MDM2 inhibitors, of anti-MDM2 antisense oligonucleotides as a novel class of anticancer agents, and suggest a potentially relevant role for the oligonucleotides when integrated with conventional treatments and/or other signaling inhibitors in novel therapeutic strategies.
 ...
PMID:Chemosensitization by antisense oligonucleotides targeting MDM2. 1572 Jan 89


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