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)

Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6, MDA7, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7, interferon (IFN)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
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PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78

Despite a prolongation of patient survival, the overall response of doxorubicin (DX) treatment on patients with hepatocellular carcinoma (HCC) remains modest. This is largely attributed to the development of tumor drug resistance either at the onset or during the course of treatment. To investigate the genetic changes associated with DX chemo-resistance, we examined the cytotoxic effect of DX on a panel of 9 HCC cell lines (HepG2, Hep3B, PLC/PRF/5, and six in-house established, HKCI-1, 2, 3 and 4, C1 and C2). The karyotypic abnormalities were examined by spectral karyotyping (SKY) and the chromosome loci defined were investigated for underlying deregulated genes by positional expression profiling. Quantitative RT-PCR was employed to verify the profiling findings, and also used to examine a number of drug resistance-related candidate genes (MDR1, MRP1, MGMT, PTEN, BCL2, BAX, TP53 and P21). Our results indicated that the cytotoxic effect of DX in cell lines exhibited IC50 values that ranged from sensitive to resistant (0.07 to 3.55 microM). While the overall chromosome aneuploidy did not correlate with DX resistance, aberrations on chromosome 10 demonstrated significant correlation with increasing IC50 (p=0.007). Positional profiling further suggested the consistent down-regulation of CGI-18 and ECHS1 on chromosome 10q. The array findings were substantiated by quantitative RT-PCR, which further pointed to a repressed ECHS1 expression in correlation with DX resistance (p=0.021). Among the candidate genes studied, an inverse relationship of P21 (p=0.034) and BAX (p=0.002) expression with DX resistance was also indicated. Our present study highlights the usefulness of multimodality approaches in identifying genetic markers, and further describes the novel finding of ECHS1 down-regulation in the DX chemo-resistance of HCC.
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PMID:Genetic alterations in doxorubicin-resistant hepatocellular carcinoma cells: a combined study of spectral karyotyping, positional expression profiling and candidate genes. 1549 26

The BCL-2 family has been implicated in the pathogenesis of various hematopoietic malignancies, including follicular non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia. To identify genes that act synergistically in BCL2-enforced leukemogenesis, we developed a murine B-cell lymphoma/leukemia model based on the IL-3-dependent Balb/C pro-B line (FL5.12). FL5.12 cells were stably transfected with antiapoptotic BCL-2 alone or in combination with proapoptotic BAX or nonfunctional mutant BAX, thereby creating various levels of imbalance within the BCL-2 family. Transfectants were intravenously injected into normal Balb/C mice. Whereas FL5.12 cells did not provoke leukemia, mice injected with stable transfectants died of leukemia over time. Disease incidence and latency time depended on the degree of imbalance in the BCL-2 family, supporting a model whereby BCL2 drives tumorigenesis. All mice presented with hepatosplenomegaly and leukemic FL5.12 cells in peripheral blood and bone marrow compartments. Leukemic conversion was accompanied by secondary genetic aberrations leading to clonal IL-3-responsive leukemia. Cellular transformation was independent of alterations in c-Myc or downstream apoptotic pathway. Leukemic clones retained a normal DNA damage response leading to elevated P53 and P21 levels and cell cycle arrest upon irradiation. In conclusion, our mouse model may prove a valuable tool to identify genes that cooperate in BCL2-enforced lymphoma/leukemogenesis.
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PMID:Novel murine B-cell lymphoma/leukemia model to study BCL2-driven oncogenesis. 1564 25

The article reviews the possible responses of liver cells to chemical insult. Both the necrosis and different ways of apoptotic death are considered. The regulatory role of BCL2/BAX proteins, p53 protein as well as other proteins modulating its activity is also described. The controlled proliferation is presented which base on transition of fully differentiated hepatocytes from the resting Go phase to GI phase of cell cycle. It is triggered by the loss of organ mass after extensive necrosis induced by xenobiotics. In this context the interrelations between the parenchymal cells (hepatocytes) and nonparenchymal cells, intercellular matrix, released growth factors are discussed. Tumorigenesis is also mentioned with special emphasis on the cell cycle control points and "run-away" from apoptosis of some cells despite the serious mistakes present in their DNA.
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PMID:[Do liver cells predict the risk of damage by chemical substances?]. 1573 96

Familial breast cancers that are associated with BRCA1 or BRCA2 germline mutations differ in both their morphological and immunohistochemical characteristics. To further characterize the molecular difference between genotypes, the authors evaluated the expression of 37 immunohistochemical markers in a tissue microarray (TMA) containing cores from 20 BRCA1, 14 BRCA2, and 59 sporadic age-matched breast carcinomas. Markers analyzed included, amog others, common markers in breast cancer, such as hormone receptors, p53 and HER2, along with 15 molecules involved in cell cycle regulation, such as cyclins, cyclin dependent kinases (CDK) and CDK inhibitors (CDKI), apoptosis markers, such as BCL2 and active caspase 3, and two basal/myoepithelial markers (CK 5/6 and P-cadherin). In addition, we analyzed the amplification of CCND1, CCNE, HER2 and MYC by FISH. Unsupervised cluster data analysis of both hereditary and sporadic cases using the complete set of immunohistochemical markers demonstrated that most BRCA1-associated carcinomas grouped in a branch of ER-, HER2-negative tumors that expressed basal cell markers and/or p53 and had higher expression of activated caspase 3. The cell cycle proteins associated with these tumors were E2F6, cyclins A, B1 and E, SKP2 and Topo IIalpha. In contrast, most BRCA2-associated carcinomas grouped in a branch composed by ER/PR/BCL2-positive tumors with a higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. In conclusion, our study in hereditary breast cancer tumors analyzing 37 immunohistochemical markers, define the molecular differences between BRCA1 and BRCA2 tumors with respect to hormonal receptors, cell cycle, apoptosis and basal cell markers.
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PMID:Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. 1577 May 21

In contrast to nodal large B-cell lymphomas, recurrent chromosomal aberrations have been studied only in a small number of cases of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL). We investigated 25 PCDLBCLs (classified according to the WHO-EORTC classification into PCDLBCL, leg-type, 8; and PCDLBCL, other, 17), using an interphase fluorescence in situ hybridization technique. All cases were analyzed for chromosomal aberrations commonly observed in nodal large B-cell lymphomas, including structural aberrations of the genes BCL2, BCL6, and c-MYC, and numerical aberrations of the chromosomes/genes 3, 7, 8, 11, 12, 13, 17, 18q, RB1, and p53. We observed genetic aberrations in 19 (76%) of 25 patients. The most frequent numerical aberrations were gains of chromosome 12 (7 of 25, 28%), 7 (5 of 25, 20%), 3 (5 of 25, 20%), 18q (3 of 25, 12%), 11 (3 of 25, 12%), X (3 of 25, 12%), and losses of chromosome/gene 17/p53 (3 of 25, 12%). BCL2, c-MYC, and BCL6 were rearranged with the IGH gene in 4 (16%), 1 (4%), and none (0%) of 25 cases, respectively. Most aberrations were homogeneously distributed among cases of PCDLBCL, leg-type and of PCDLBCL, other, cases located on the leg or at other body sites, cases with round and cleaved cell morphology, and Bcl-2+ and Bcl-2- cases. These results suggest that PCDLBCLs show similar chromosomal aberrations irrespective of classification, anatomic site, cell morphology, and Bcl-2 expression, and that many similarities between primary cutaneous and nodal diffuse large B-cell lymphomas can be observed.
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PMID:Genetic aberrations in primary cutaneous large B-cell lymphoma: a fluorescence in situ hybridization study of 25 cases. 1583 92

The effects of the separate and combined application of hypoxia and antisense oligonucleotides (ASO) against hypoxia inducible factor 1alpha (HIF1A) on cancer cells were examined. Experiments were carried out on human ovarian carcinoma cells in four series: (1) control [Normoxia (5% CO2 in air), no treatment], (2) hypoxia (1% O2, 5% CO2, and 94% N2 for 48 h), (3) treatment with ASO targeted to HIF1A (48 h), and (4) combined action of hypoxia and ASO. After treatment, the following processes and factors were monitored: apoptosis, cellular metabolism and viability, expression of genes encoding HIF1A, von Hippel-Lindau tumor suppressor protein (VHL), and genes responsible for cell death induction and antiapoptotic defense (P53, BCL2, BAX, and caspases 9 and 3). Expression of caspase 9 and HIF1A protein was confirmed by Western blotting. Liposomes were used as a delivery system of HIF1A ASO. It was found that hypoxia alone significantly disturbed cellular metabolism, reducing the level of respiration by 50% when compared with control. Hypoxia induced apoptosis by upregulating the P53-, BAX-, and caspase-dependent cell death pathways, while activating cellular antiapoptotic defense by the overexpression of BCL2 protein. Both opposing effects were dependent on the overexpression of hypoxia inducible factor. We conclude that hypoxia induces a bimodal effect, simultaneously promoting cell death and activating cellular resistance. The downregulation of HIF1A promoted cell death induction and prevented activation of cellular defense by hypoxia. This suggests that HIF1A is a potential candidate for anticancer therapeutic targeting.
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PMID:Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. 1583 12

Activation of an oncogene via its juxtaposition to the IGH locus by a chromosomal translocation or, less frequently, by genomic amplification is considered a major mechanism of B-cell lymphomagenesis. However, amplification of an IGH/oncogene fusion, coined a complicon, is a rare event in human cancers and has been associated with poor outcome and resistance to treatment. In this article are descriptions of two cases of germinal-center-derived B-cell lymphomas with IGH/BCL2 fusion that additionally displayed amplification of an IGH/MYC fusion. As shown by fluorescence in situ hybridization, the first case contained a IGH/MYC complicon in double minutes, whereas the second case showed a BCL2/IGH/MYC complicon on a der(8)t(8;14)t(14;18). Additional molecular cytogenetic and mutation analyses revealed that the first case also contained a chromosomal translocation affecting the BCL6 oncogene and a biallelic inactivation of TP53. The second case harbored a duplication of REL and acquired a translocation affecting IGL and a biallelic inactivation of TP53 during progression. Complicons affecting Igh/Myc have been reported previously in lymphomas of mouse models simultaneously deficient in Tp53 and in genes of the nonhomologous end-joining DNA repair pathway. To the best of our knowledge, this is the first time that IGH/MYC complicons have been reported in human lymphomas. Our findings imply that the two mechanisms resulting in MYC deregulation, that is, translocation and amplification, can occur simultaneously.
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PMID:Amplification of IGH/MYC fusion in clinically aggressive IGH/BCL2-positive germinal center B-cell lymphomas. 1585 72

Pluronic block copolymer P85 (P85) sensitizes multidrug resistant (MDR) cancer cells resulting in the increase of cytotoxic activity of antineoplastic agents. This effect is attributed to the inhibition of the most clinically relevant drug efflux transporter, P-glycoprotein (Pgp), through the combined ATP depletion and inhibition of Pgp ATPase activity. The present study elucidates effects of an anticancer agent, doxorubicin (Dox), formulated with P85 on drug-induced apoptosis in MDR cancer cells. Early and late stages of apoptosis were detected by Annexin V and TUNEL methods, respectively. In parallel experiments, the expression of genes related to apoptosis, BCL2, BCLXL, BAX, P53, APAF1, Caspase 3, and Caspase 9, was determined by RT-PCR. The obtained data suggest that Dox/P85 formulation induces apoptosis in the resistant cancer cells more efficiently than free Dox. The treatment of the cells with Dox alone simultaneously activated a proapoptotic signal and an antiapoptotic cellular defense. Therefore, the apoptosis induction by Dox was substantially limited. In contrast, the treatment of the cells with Dox/P85 formulation significantly enhanced the proapoptotic activity of the drug and prevented the activation of the antiapoptotic cellular defense. This is likely to result in the stronger cytotoxic response of the resistant cells to the Dox/P85 formulation compared to the free drug.
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PMID:Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells. 1593

Clonally related composite lymphomas of Hodgkin's lymphoma (HL) and Non-Hodgkin's lymphoma (NHL) represent models to study the multistep transformation process in tumorigenesis and the development of two distinct tumors from a shared precursor. We analyzed six such lymphomas for transforming events. The HLs were combined in two cases with follicular lymphoma (FL), and in one case each with B-cell chronic lymphocytic leukemia, splenic marginal zone lymphoma, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). In the HL/FL and HL/MCL combinations, BCL2/IGH and CCND1/IGH translocations, respectively, were detected in both the HL and NHL. No mutations were found in the tumor suppressor genes FAS, NFKBIA and ATM. The HL/DLBCL case harbored clonal replacement mutations of the TP53 gene on both alleles exclusively in the DLBCL. In conclusion, we present the first examples of molecularly verified IgH-associated translocations in HL, which also show that BCL2/IGH or CCND1/IGH translocations can represent early steps in the pathogenesis of composite HL/FL or HL/MCL. The restriction of the TP53 mutations to the DLBCL in the HL/DLBCL case exemplifies a late transforming event that presumably happened in the germinal center and affected the fate of a common lymphoma precursor cell towards development of a DLBCL.
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PMID:Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas. 1597 55


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