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)

The t(9;14)(p13;q32) translocation is associated with approximately 50% of lymphoplasmacytoid lymphoma (LPL), a subtype of B-cell non-Hodgkin's lymphoma (NHL). We cloned the chromosomal breakpoint of der (14) from an LPL case (1052) and showed that it involved a junction between 9p13 and the switch micro region of the Ig heavy chain locus (IgH) on 14q32. Using a YAC contig spanning 1.5 megabase (Mb), we determined that the 9p13 breakpoint in one case (1052) mapped within a 270-kb restriction fragment containing two previously reported 9p breakpoints associated with a alpha-heavy chain disease case (MAL) and KI-1 positive diffuse large cell lymphoma (DLCL) cell line (KIS-1). The same fragment also contained the PAX-5 gene which encodes a B-cell specific transcription factor involved in the control of B-cell proliferation and differentiation. The breakpoints of KIS-1 and 1052 were mapped within the 5' noncoding region of PAX-5, while the 9p13 breakpoint of MAL mapped 230 to 270 kb upstream to PAX-5. In all three cases, the translocation caused the juxtaposition of the PAX-5 gene to the IgH locus in the opposite direction of transcription. When compared with six other DLCL cell lines lacking t(9;14)(p13;q32), the KIS-1 cell line showed an 11-fold overexpression of PAX-5 mRNA and a significantly reduced expression of the p53 gene, which is normally regulated by PAX-5. Moreover, metaphase and interphase fluorescence in situ hybridization (FISH) analysis using a YAC clone spanning 1 Mb including the PAX-5 as a probe identified chromosomal translocations in 5 of 7 cases carrying 9p13 translocations. These findings suggest that the PAX-5 gene is the target of the t(9;14) in LPL whereby its expression may be deregulated by juxtaposition to IgH regulatory elements, thus contributing to lymphomagenesis.
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PMID:The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. 894 44

Spi-1/PU.1 is a myeloid- and B-cell specific transcription factor which is also involved in Friend virus-induced murine erythroleukemia. The pre-leukemic phase of Friend erythroleukemia results from activation of the erythropoietin receptor (EpoR) by the spleen focus forming virus (SFFV) envelope glycoprotein, followed by the emergence of leukemic clones characterized by overexpression of Spi-1 and mutation of the p53 tumor suppressor gene. We developed a heterologous system to analyze the contribution of these alterations to the induction of primary erythroblast transformation. Avian erythroblasts expressing the activated mouse EpoR(R129C) differentiated into erythrocytes in response to hEpo. Expression of Spi-1 in these cells inhibited this ability to differentiate and rescued the cells from the apoptotic cell death program normally induced upon hEpo withdrawal. Although devoid of any effect by itself, a mutant p53 cooperated with Spi-1 and EpoR(R129C) to reinforce both phenotypes. Analysis of erythroblasts co-expressing Spi-1 and the wild-type mouse EpoR showed that differentiation arrest and inhibition of apoptosis depended on specific cooperation between Spi-1 and EpoR(R129C). This cooperation was also required to induce the sustained proliferation of differentiation-blocked erythroblasts in response to ligand activation of the endogenous tyrosine kinase receptor c-Kit. These results show that Spi-1/PU.1 requires signals emanating from specific cytokine and growth factor receptors to affect the survival, proliferation and differentiation control of primary erythroblasts. They also suggest that the function of Spi-1/PU.1 in the late phase of Friend leukemia requires specific signaling from the gp55-modified EpoR generated during the early phase of the disease.
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PMID:Cooperation of Spi-1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo-dependent differentiation in primary erythroblasts and induces their Kit ligand-dependent proliferation. 931 23

Low grade B-cell non-Hodgkin's lymphomas (B-NHL) represent a markedly heterogeneous group of lymphoproliferative disorders, including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CCL/SLL), lymphoplasmacytoid lymphoma (LPL), follicular lymphoma (FL), mucosa-associated lymphoid tissue lymphoma (MALTL), and splenic lymphoma with villous lymphocytes (SLVL). The molecular pathogenesis of low grade B-NHL is characterized by distinct genetic pathways which selectively associate with each clinicopathologic category. At diagnosis, B-CLL/SLL frequently display deletions of 13q14 and trisomy 12, whereas evolution to Richter's syndrome associates with disruption of p53. LPL carries t(9;14)(p13;q32) in 40-50% of the cases, leading to the deregulated expression of the PAX-5 gene. FL consistently harbors rearrangements of BCL-2 independent of the cytologic variant. With time, a fraction of FL cases accumulates mutations of p53 and evolves into a high grade B-NHL. Low grade MALTL are characterized by the frequent occurrence of trisomy 3 and, occasionally, by p53 mutations. SLVL carries p53 mutations in a fraction of cases. The identification of distinct genetic categories among low grade B-NHL may help in the therapeutic stratification of these disorders. In addition, genetic lesions of low grade B-NHL have proved to be a useful molecular marker for monitoring minimal residual disease.
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PMID:Molecular pathways in low grade B-cell lymphoma. 957 Jun 87

The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role for Pax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin's lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Smicro promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed that PAX-5 transcription was upregulated due to efficient initiation at the Smicro promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distal PAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Emicro; enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target gene p53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increased PAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.
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PMID:Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma. 980 80

Indolent lymphomas are a markedly heterogeneous group of lymphoproliferative disorders including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The molecular pathophysiology of indolent lymphoma is characterized by distinct genetic pathways which selectively associate with different clinico-pathologic categories of the disease. At diagnosis, B-cell chronic lymphocytic leukemia frequently display deletions of 13q14, trisomy 12 and alterations of the ATM gene, whereas evolution to Richter's syndrome is associated with disruption of p53. Lymphoplasmacytoid lymphoma carries t(9;14) (p13;q32) in approximately 50% of cases, leading to the deregulated expression of the PAX-5 gene. Follicular lymphoma consistently harbors rearrangement of BCL-2. With time, a fraction of follicular lymphoma accumulates mutations of p53 and of p16 and evolves into a high grade lymphoma. MALT-lymphoma frequently associates with alterations of API2/MLT and, in some cases, of p53, BCL-6 and BCL-10. Studies of genotypic and phenotypic markers of histogenesis have shown that mantle cell lymphoma and a fraction of B-CLL/SLL derive from naive B-cells, whereas follicular lymphoma, lymphoplasmacytoid lymphoma and MALT-lymphoma originate from germinal center (GC) or post-GC B-cells. The identification of distinct genetic categories of indolent lymphoma may help in the therapeutic stratification of these disorders. In addition, genetic lesions of indolent lymphoma provide useful molecular markers for disease monitoring by high sensitivity techniques.
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PMID:Molecular pathophysiology of indolent lymphoma. 1068 15

In the literature, sufficient attention has not been paid to the precise subcellular localization of immunohistochemical signals, the knowledge of which is essential for proper interpretation of immunostains and distinction of genuine staining from biotin-associated or other nonspecific stainings. The subcellular localization of the signals can in fact be easily deduced from the known biologic or ultrastructural characteristics of the antigens. Extracellular antigens obviously are located in the extracellular compartment. Cellular antigens fall into 3 major groups: membranous, nuclear, and cytoplasmic. Membranous antigens include cell adhesion molecules (such as E-cadherin, N-CAM), cell surface/transmembrane receptors and proteins (such as tyrosine kinase receptors, most leukocyte antigens, CD10, CEA), and molecules linking surface molecules to cytoskeleton (such as beta-catenin, dystrophin). Nuclear antigens include cell cycle-associated proteins (such as cyclins, p16, Ki-67), nuclear enzymes (such as TdT), transcription factors (such as TTF-1, CDX-2, myogenin, PAX-5), tumor suppressor gene products (such as p53, p63, WT1, Rb), steroid hormone receptors (such as ER, PR), calcium-binding proteins (such as S-100 protein, calretinin), and some viral proteins (such as CMV, herpes). Cytoplasmic antigens can take up a granular pattern due to localization in organelles, granules, or secretory vesicles (such as chromogranin, hormones, lysozyme, HMB-45), fibrillary pattern attributable to the filamentous nature of the molecules (intermediate filaments and microfilaments), or diffuse or patchy pattern due to localization in the cytosol or large vesicles (such as myoglobin, albumin, thyroglobulin). Aberrant localization of the molecules, when present, can provide important insight into disease processes and aid in their diagnosis, such as loss of membranous E-cadherin expression in lobular breast carcinoma, aberrant nuclear localization of beta-catenin in colorectal adenocarcinoma, pattern of ALK staining in anaplastic large cell lymphoma correlating with the different types of chromosomal translocations, presence of additional cytoplasmic CD10 staining in the enterocytes indicative of microvillous inclusion disease, and "reversed" staining for EMA in micropapillary mammary carcinoma.
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PMID:Subcellular localization of immunohistochemical signals: knowledge of the ultrastructural or biologic features of the antigens helps predict the signal localization and proper interpretation of immunostains. 1530 32

Plasmablastic lymphoma is an aggressive neoplasm that shares many cytomorphologic and immunophenotypic features with plasmablastic plasma cell myeloma. However, plasmablastic lymphoma is listed in the World Health Organization (WHO) classification as a variant of diffuse large B-cell lymphoma. To characterize the relationship between plasmablastic lymphoma and plasmablastic plasma cell myeloma, we performed immunohistochemistry using a large panel of B-cell and plasma cell markers on nine cases of plasmablastic lymphoma and seven cases of plasmablastic plasma cell myeloma with and without HIV/AIDS. The expression profiles of the tumor suppressor genes p53, p16, and p27, and the presence of Epstein-Barr virus (EBV) and human herpes virus type 8 (HHV-8) were also analyzed. All cases of plasmablastic lymphoma and plasmablastic plasma cell myeloma were positive for MUM1/IRF4, CD138, and CD38, and negative for CD20, corresponding to a plasma cell immunophenotype. PAX-5 and BCL-6 were weakly positive in 2/9 and 1/5 plasmablastic lymphomas, and negative in all plasmablastic plasma cell myelomas. Three markers that are often aberrantly expressed in cases of plasma cell myelomas, CD56, CD4 and CD10, were positive in 5/9, 2/5, and 6/9 plasmablastic lymphomas, and in 3/7, 1/5, and 2/7 plasmablastic plasma cell myelomas. A high Ki-67 proliferation index, overexpression of p53, and loss of expression of p16 and p27 were present in both tumors. No evidence of HHV-8 infection was detected in either neoplasm. The only significant difference between plasmablastic lymphoma and plasma cell myeloma was the presence of EBV-encoded RNA, which was positive in all plasmablastic lymphoma cases tested and negative in all plasma cell myelomas. In conclusion, most cases of AIDS-related plasmablastic lymphoma have an immunophenotype and tumor suppressor gene expression profile virtually identical to plasmablastic plasma cell myeloma, and unlike diffuse large B-cell lymphoma. These results do not support the suggestion in the WHO classification that plasmablastic lymphoma is a variant of diffuse large B-cell lymphoma.
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PMID:Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. 1557 69

MPP(+) (1-methyl-4-phenylpyridinium; the active metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)) depletes dopamine (DA) content and elicits cell death in PC12 cells. However, the mechanism of MPP(+)-induced neurotoxicity is still unclear. In this study, the dose response and time-course of MPP(+)-induced DA depletion and decreased cell viability were determined in nerve growth factor (NGF)-differentiated PC12 cells. The alteration of transcription factors (TFs) induced by MPP(+) from a selected dose level and time point was then evaluated using protein/DNA-binding arrays. K-means clustering analysis identified four patterns of protein/DNA-binding changes. Three of the 28 TFs identified in PC12 cells increased by 100% (p53, PRE, Smad SBE) and 2 decreased by 50% (HSE, RXR(DR1)) of control with MPP(+) treatment. In addition, three TFs decreased within the range of 33-50% (TFIID, E2F1, CREB) and two TFs increased within the range of 50-100% (PAX-5, Stat4). An electrophoretic mobility shift assay (EMSA) was used to confirm the changes of p53 and HSE. The observed changes in TFs correlated with the alterations of DA and cell viability. The data indicates that selective transcription factors are involved in MPP(+)-induced neurotoxicity and it provides mechanistic information that may be applicable to animal studies with MPTP and clinical studies of Parkinson's disease.
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PMID:Selective alterations of transcription factors in MPP+-induced neurotoxicity in PC12 cells. 1611 30

Primary mediastinal large B-cell lymphoma (PMLBCL) is a unique type of B-cell lymphoma probably arising from a putative thymic medulla B-cell. It constitutes 6-10% of all diffuse large B-cell lymphomas (DLBCL), occurring more often in young females. PMLBCL is characterized by a diffuse proliferation of medium to large B-cells associated with sclerosis and a degree of compartmentalisation. Its main molecular characteristics include: gains in 9p segments, p53 mutations, BCL-2 and MAL gene over-expression, somatic mutations of IgVH genes, BCL-6, PIM-1, PAX-5, RhoH/TTF, and c-MYC, and constitutional NF-kappaB activation. The gene expression signature of PMLBCL seems to be much closer to classic Hodgkin lymphoma than to DLBCL. PMLBCL is characterized by a locally invasive anterior mediastinal mass, often producing cough, chest pain, dyspnea, and superior vena cava syndrome. Most PMLBCL patients have stage I-II, bulky disease, with pleural or pericardial effusions in a third of cases. Systemic symptoms, mainly fever or weight loss, are present in <20% of cases; increased LDH levels are observed in 70-80% of cases. Treatment with CHOP regimen followed by radiation therapy was associated with a 5-year survival of 65%. Apparently better results have been reported with third-generation weekly alternating regimens followed by radiation therapy. Any recurrence is almost always seen in the first 2 years of follow-up, and distant relapses tend to involve extranodal organs. Features associated with poor prognosis are poor performance status, pericardial effusion, bulky disease, high serum LDH at diagnosis, and a compromised dose-intensity of anthracycline and cyclophosphamide.
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PMID:Primary mediastinal large B-cell lymphoma. 1877 28

Survival in Hodgkin lymphoma (HL) has significantly increased, and most relapses occur in the first 2 years. We analyzed the proportion of relapses occurring after 5 years, the method of detection, and survival in the database of patients with HL in our hospital (1967-2005). We undertook a retrospective study of clinical and molecular characteristics with the use of 12 different antibodies (Abs): CD30, CD15, CD20, CD3, BCL-2, BCL-6, CD57, EMA, p53, Ki-67, Aurora kinase A, and PAX-5. We studied 534 patients with HD and found 150 relapses (28%), 30 of which occurred 5 years after the end of treatment. The relapses were detected during a scheduled appointment in 16 (54%) asymptomatic patients. Seven of 30 patients relapsed with a different histological type. There were no statistically significant differences in survival between those patients with a late relapse and new remission and those who never relapsed. None of the molecular markers were associated with relapse. Long-term survival was not significantly different in relapsed patients with remission after treatment compared with patients who never relapsed. We need to maintain active follow-up in order to detect late and recoverable relapses.
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PMID:Late relapses in Hodgkin lymphoma: a clinical and immunohistochemistry study. 2062 26


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