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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PCR amplification of fragments of transcribed (beta-actin, p53) and nontranscribed (IgE, heavy chain) genes in brain and spleen DNA from gamma-irradiated and unirradiated 2- and 28-month-old rats was studied. The amplification levels of fragments of these genes in DNA from old rats were substantially lower than those from young rats, which suggested that these gene fragments in old-rat DNA contained lesions blocking thermostable polymerase in PCR. The beta-actin and IgE gene fragments of spleen DNA from old rats exhibited a significantly higher level of lesions inhibiting Tth polymerase compared to analogous fragments of brain DNA from the same animals. DNA from the tissues of gamma-irradiated rats showed the amount of damage inhibiting amplification to be dependent on animal age and the postirradiation time before DNA isolation. As judged from the changes in the amplification level of gene fragments, there was no preferential fast repair of lesions in the actively transcribed gene beta-actin compared to the nontranscribed gene IgE (heavy chain) in the brain and spleen of gamma-irradiated young and old rats. The amplification results suggest that equal amounts of DNA lesions were repaired in the brain of both old and young rats during the first 0.5 h of the postirradiation time (fast-repair phase), whereas in the subsequent postirradiation period over 5 h (slow-repair phase), the efficiency of damage elimination in the brain DNA of old rats was markedly lower. As for the spleen tissue, the elimination of lesions blocking Tth polymerase was much lower in old gamma-irradiated animals for both of the repair phases.
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PMID:PCR assay of DNA damage and repair at the gene level in brain and spleen of gamma-irradiated young and old rats. 1042 39

Damage and repair of DNA isolated from brain and spleen of gamma-irradiated rats were assayed using the polymerase chain reaction (PCR) method. Damage produced by gamma-radiation in DNA in cells of these tissues of exposed animals was shown to block PCR with the Tth polymerase. This blockage was noted as a decrease in the level of amplification of the fragments of a transcribed gene (beta-actin), an inducible gene (p53), and a nontranscribed one (IgE, heavy chain). The most pronounced decrease in the amplification of the gene fragments was observed on the DNA template isolated from rats immediately after their gamma-irradiation. When DNA was isolated 0.5-5.0 h after exposure, the amplification level was restored, no matter what transcription activity the genes possessed. For comparison, we used in PCR in vitro gamma-irradiated DNA as well as DNA templates with UV-damage, 8-oxy-2;-deoxyguanosine (8-O-dG), and apurinic sites (AP-sites). We found that gamma- and UV-irradiated DNA as well as DNA with AP-sites blocked the Tth polymerase in PCR, whereas 8-O-dG did not effect the level of PCR amplification of gene fragments. The observed changes in the level of PCR amplification of genes on the DNA template from tissues of gamma-irradiated animals are due to various radiation-induced lesions capable of blocking the Tth polymerase. The results show that the PCR method can be used for assaying the integral DNA damage and repair in cells from irradiated animals.
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PMID:Estimation of DNA damage and repair in tissues of gamma-irradiated animals using the polymerase chain reaction. 1061 40

An understanding of the molecular biology of B-cell chronic lymphocytic leukemia (B-CLL) has led to the appreciation that several different B-cell diseases are represented under this name. Variability in the bcl-2 family of proteins, p53 mutation, or the presence of various chromosomal abnormalities corresponds to variability of the clinical course of disease and response to therapy. Differential expression of cell surface adhesion molecules by B-CLL cells have also been shown to influence clinical outcome, as have the expression of immune regulatory molecules (eg, CD80, CD40R, CD27 and CD79b). Recent work studying immunoglobulin-heavy chain gene rearrangement postulates at least two subsets of B-CLL originating from different stages of B-cell development and following different clinical courses. The knowledge that B-CLL is the final consequence of many different molecular perturbations may allow the development of chemotherapies, immunotherapies, and gene therapies that target the specific molecular defect in a given case of B-CLL.
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PMID:Update on the biology of chronic lymphocytic leukemia. 1068 25

We describe the establishment and characterization of a new multiple myeloma (MM) cell line, KYdelta-1, which expressed delta/kappa type immunoglobulin (Ig). The patient was a 65-year-old woman with MM, who presented extramedullary dissemination, lymphadenopathy and short survival. The KYdelta-1 cell line was derived from the pleural fluid obtained in the terminal phase of the disease. The cells expressed delta/kappa Ig in the cytoplasm, and CD10, CD29, CD33, CD38, CD44, CD54, and HLA-DR antigens on the cell surface. Chromosomal analysis revealed two independent translocations, t(3;14)(p21;q32) and t(3;11)(p21;q13), which were confirmed by fluorescence in situ hybridization using chromosome painting probes. Reverse transcriptase-mediated polymerase chain reaction (PCR) and Northern blot analyses demonstrated overexpression of the CCND1 gene, suggesting alteration of the BCL1-CCND1 locus. We thus performed long-distance inverse PCR using nested primers for the Calpha constant region of immunoglobulin heavy chain gene (IGH) and obtained a clone that encompassed the 11q13/IGH fusion. Nucleotide sequencing determined that the fusion occurred at the Salpha2 switch region and at the centromeric side of the major translocation cluster of BCL1. The other IGH allele consisted of a VDJ complex that was adjacent to the Cdelta constant gene, indicating that a class switch-like mechanism from the C(mu) to Cdelta was involved in the production of the Ig delta heavy chain. Point mutations within the P53 and N-RAS genes were presumably related to the rapidly progressive disease in this particular MM patient.
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PMID:Establishment and characterization of a new human myeloma cell line, KYdelta-1, producing the delta/kappa type immunoglobulin. 1167 73

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease involving more than one molecular mechanism that leads to the transformation of CD5(+) B cells at either the pregerminal or postgerminal center stage of differentiation. It was previously demonstrated that ataxia telangiectasia mutated (ATM) gene mutations can occur in B-CLL and cause a defect in the p53 pathway. Here the role of ATM mutations in the pathogenesis of B-CLL is addressed. Of 50 B-CLL tumors with fully analyzed ATM and TP53, 16 had ATM mutations. Six of 50 B-CLLs showed mutations in TP53 and the remaining 28 tumors had wild-type ATM or TP53. No tumor had both ATM and TP53 mutations. Remarkably, all 16 ATM mutant B-CLLs showed the absence of somatic variable region heavy chain hypermutation indicating a pregerminal center cell origin and a common pathogenesis for these tumors. Furthermore, in 5 of the 16 B-CLLs, ATM mutation preceded the transformation stage of differentiation. At the cellular level, ATM mutant tumors exhibited a deficient ATM-dependent p53 response to gamma irradiation, failure to up-regulate TRAIL-R2, a downstream target that links irradiation-induced p53 response with apoptosis, and an inability to repair induced chromosome breaks. Mantle cell lymphoma (MCL) is also of pregerminal center origin and ATM mutations are frequent in this malignancy. It is concluded that ATM is likely to play an important role at the pregerminal center stage and a model is proposed where loss of ATM function during B-cell ontogeny drives B-CLL tumorigenesis in pregerminal B cells by a dual defect in p53 damage response and repair of chromosome breaks.
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PMID:Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage. 1175 85

Metastasis-associated protein S100A4 (Mts1) induces invasiveness of primary tumors and promotes metastasis. S100A4 belongs to the family of small calcium-binding S100 proteins that are involved in different cellular processes as transducers of calcium signal. S100A4 modulates properties of tumor cells via interaction with its intracellular targets, heavy chain of non-muscle myosin and p53. Here we report identification of a new molecular target of the S100A4 protein, liprin beta1. Liprin beta1 belongs to the family of leukocyte common antigen-related (LAR) transmembrane tyrosine phosphatase-interacting proteins that may regulate LAR protein properties via interaction with another member of the family, liprin alpha1. We showed by the immunoprecipitation analysis that S100A4 interacts specifically with liprin beta1 in vivo. Immunofluorescence staining demonstrated the co-localization of S100A4 and liprin beta1 in the cytoplasm and particularly at the protrusion sites of the plasma membrane. We mapped the S100A4 binding site at the C terminus of the liprin beta1 molecule between amino acid residues 938 and 1005. The S100A4-binding region contains two putative phosphorylation sites by protein kinase C and protein kinase CK2. S100A4-liprin beta1 interaction resulted in the inhibition of liprin beta1 phosphorylation by both kinases in vitro.
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PMID:Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1). 1183 60

The c-Myc oncoprotein is strongly implicated in B-cell neoplasms such as human Burkitt lymphomas and mouse plasmocytomas. Transgenic mice in which the myc gene is juxtaposed to an immunoglobulin enhancer (E(mu)-myc) also develop B-cell lymphomas, but relatively late in life. In addition, these neoplasms are invariably clonal, suggesting the involvement of additional mutations. Such mutations frequently affect the p53 tumour suppressor gene or its positive regulator Arf, hinting that inactivation of the p53 pathway might be the second hit required for the progression towards malignancy. However, even tumours arising in E(mu)-myc/Arf-null animals are thought to be clonal. This observation raised doubts whether overexpression of Myc in p53-null B-cell precursors is sufficient for tumorigenesis. To address this question, we have established a new, non-transgenic mouse model of B-lymphoma. This model is based on isolation of primary bone marrow (BM) cells, admixing them with packaging cells producing a Myc-encoding retrovirus (LMycSN), and subcutaneous injection into a host with which BM cells are syngeneic. Predictably, wild type BM cells infected in vivo by LMycSN were not tumorigenic. However, LMycSN-infected p53-null BM cells readily gave rise to B-cell lymphomas composed predominantly of late pro-B/small pre-B-cells. In these tumours, heavy chain gene rearrangements were analysed using two independent PCR-based assays. All neoplasms with DJ-rearrangements were found to be polyclonal. This result suggests that inactivation of p53 and overexpression of Myc is all that is necessary for the development of full-fledged B-lymphomas. Our model would also be instrumental in assessing the transforming potential of Myc mutants and in studying cooperation between Myc and other oncogenes.
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PMID:A non-transgenic mouse model for B-cell lymphoma: in vivo infection of p53-null bone marrow progenitors by a Myc retrovirus is sufficient for tumorigenesis. 1189 25

The genetic characterization of chronic lymphocytic leukemia (CLL) has made significant progress over the past few years. While conventional cytogenetic analyses only detected chromosome aberrations in 40-50% of cases, new molecular cytogenetic methods, such as fluorescence in situ hybridization (FISH), have greatly enhanced our ability to detect chromosomal abnormalities in CLL. Today, genomic aberrations are detected in over 80% of CLL cases. Genes potentially involved in the pathogenesis were identified with ATM in a subset of cases with 11q deletion and p53 in cases with 17p13 deletion. For the most frequent aberration, the deletion 13q14, candidate genes have been isolated. Genetic subgroups with distinct clinical features have been identified. 11q deletion is associated with marked lymphadenopathy and rapid disease progression. 17p deletion predicts for treatment failure with alkylating agents, as well as fludarabine and short survival times. In multivariate analysis 11q and 17p deletions provided independent prognostic information. Recently, another important issue of genetic risk classification in CLL was identified with the mutation status of the immunoglobulin variable heavy chain genes (V(H)). CLL cases with unmutated V(H) show more rapid disease progression and shorter survival times. Whether CD38 expression can serve as a surrogate marker for V(H) mutation status is currently discussed controversially. V(H) mutation status and genomic abnormalities, such as 17p and 11q deletion, have recently been shown to be related to each other, but were of independent prognostic information in multivariate analysis. Moreover, genomic aberrations and V(H) mutation status appear to give prognostic information irrespective of the clinical stage and may therefore allow a risk assessment for individual patients early in the course of their disease.
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PMID:Genetics of chronic lymphocytic leukemia: genomic aberrations and V(H) gene mutation status in pathogenesis and clinical course. 1204 Apr 31

Despite the advances in our knowledge of myeloma cell biology, our understanding of myeloma pathogenesis is still incomplete. In this review, we present a summary of the cellular and molecular aspects of B-cell development and immunoglobulin (lg) gene rearrangement which have been important in defining the characteristics of the myeloma plasma cell (MPC). The PMC has undergone variable gene recombination, somatic hypermutation and isotype switching, and is therefore at a postgerminal center stage of development. The finding of preswitch clonal cells and isotype variants have raised interesting questions about the cell of origin of myeloma, for which no conclusive data is as yet available. However much information has been obtained about the chromosomal and genetic aberrations in myeloma, including monosomy 13, Ig heavy chain (IgH) switch region translocations, numerical abnormalities and a multitude of heterogeneous changes. A variety of techniques have been developed to overcome the insensitivity of conventional karyotyping, utilizing molecular cytogenetic strategies ranging from the delineation of precise loci by fluorescent in situ hybridization, a more "global" assessment of the genome by multicolor spectral karyotyping, to the quantitation of chromosomal material of specific origin by comparative genomic hybridization. Whether the abnormalities detected represent oncogenic insults, are involved in disease progression or are simply "by-products" of genetic instability is still unclear. For IgH translocations, the role of candidate genes such as Cyclin D1 and FGFR3 has been studied extensively by quantitating their expression and assessment of their oncogenicity (e.g. for FGFR3) in animal models. The significance of other aberrations such as c-myc, ras and p53 has also been investigated. With the advent of oligonucleotide microarrays, the expression of thousands of genes can be efficiently examined. So far, this approach seems promising in defining subgroups of different disease behavior, and may highlight specific genes and molecular mechanisms which are important in myeloma pathogenesis.
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PMID:The biology and cytogenetics of multiple myeloma. 1261 99

The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.
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PMID:Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. 1498 23


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