Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hodgkin and Reed-Sternberg (HRS) cells represent the malignant cells in classical Hodgkin lymphoma (HL). Because their immunophenotype cannot be attributed to any normal cell of the hematopoietic lineage, the origin of HRS cells has been controversially discussed, but molecular studies established their derivation from germinal center B cells. In this study, gene expression profiles generated by serial analysis of gene expression (SAGE) and DNA chip microarrays from HL cell lines were compared with those of normal B-cell subsets, focusing here on the expression of B-lineage markers. This analysis revealed decreased mRNA levels for nearly all established B-lineage-specific genes. For 9 of these genes, lack of protein expression was histochemically confirmed. Down-regulation of genes affected multiple components of signaling pathways active in B cells, including B-cell receptor (BCR) signaling. Because several genes down-regulated in HRS cells are positively regulated by the transcriptional activator Pax-5, which is expressed in most HRS cells, we studied HL cell lines for mutations in the Pax-5 gene. However, no mutations were found. We propose that the lost B-lineage identity in HRS cells may explain their survival without BCR expression and reflect a fundamental defect in maintaining the B-cell differentiation state in HRS cells, which is likely caused by a novel, yet unknown, pathogenic mechanism.
 ...
PMID:Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. 1239 31

LMP2A is consistently detected in Hodgkin's lymphoma, nasopharyngeal carcinoma and has also been detected in Burkitt's lymphoma. Interestingly, LMP2A is detected in the absence of the transcriptional activator EBNA2, suggesting that an alternative mechanism is responsible for LMP2A expression. The intracellular domain of Notch (Notch-IC) and EBNA2 are functional homologs and recent microarray analysis indicates that LMP2A may constitutively activate the Notch pathway in vivo. Coupled with evidence that Notch-IC can bind to and activate the LMP2A promoter, we hypothesized that expression of LMP2A results in the constitutive activation of the Notch pathway to auto-regulate its promoter. Our data indicate that LMP2A constitutively activates the Notch pathway in B cells and epithelial cells. Expression of LMP2A alone is sufficient to activate its own expression and the amino-terminal signaling domain is required as LMP2B is unable to activate the LMP2A promoter. In addition, point mutations in tyrosines 31, 101 and 112 each results in a significant decrease in LMP2A promoter activation. Deletion of the RBP-Jkappa consensus sequences results in a significant decrease in promoter activity. The observation that LMP2A activates its own promoter suggests that LMP2A exploits the Notch pathway in order to control its own expression and may explain EBNA2-independent expression of LMP2A in EBV-associated malignancies.
 ...
PMID:An auto-regulatory loop for EBV LMP2A involves activation of Notch. 1798 Mar 97

Epstein-Barr virus (EBV) infection can modify the cytokine expression profiles of host cells and determine the fate of those cells. Of note, expression of interleukin-13 (IL-13) may be detected in EBV-associated Hodgkin lymphoma and the natural killer (NK) cells of chronic active EBV-infected patients, but its biologic role and regulatory mechanisms are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells early during EBV infection. Furthermore, the EBV lytic protein, Zta (also known as the BZLF-1 product), which is a transcriptional activator, was found to induce IL-13 expression following transfection. Mechanistically, induction of IL-13 expression by Zta is mediated directly through its binding to the IL-13 promoter, via a consensus AP-1 binding site. Blockade of IL-13 by antibody neutralization showed that IL-13 is required at an early stage of EBV-induced proliferation and for long-term maintenance of the growth of EBV immortalized lymphoblastoid cell lines (LCLs). Thus, Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of EBV-associated lymphoproliferative disorders, such as posttransplantation lymphoproliferative disease (PTLD) and Hodgkin lymphoma.
 ...
PMID:EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. 1941 11

Anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive non-Hodgkin lymphoma of T/null immunophenotype that is most prevalent in children and young adults. The normal cellular counterpart of this malignancy is presumed to be the cytotoxic T lymphocyte (CTL), and this presumption is partly based on the observation that these tumour cells often express cytotoxic granules containing Granzyme B (GzB) and Perforin. Chromosomal translocations involving the gene encoding for the ALK tyrosine kinase are also characteristic of ALK+ ALCL, and the resulting fusion proteins (e.g. NPM-ALK) initiate signalling events important in ALK+ ALCL pathogenesis. These events include the elevated expression of JunB; an AP-1 family transcription factor that promotes ALK+ ALCL proliferation. In this report we demonstrate that JunB is a direct transcriptional activator of GzB and that GzB transcription is also promoted by NPM-ALK. We found that Perforin expression was not regulated by JunB, but was promoted by NPM-ALK in some cell lines and inhibited by it in others. In conclusion, our study makes the novel observation that signalling through NPM-ALK and JunB affect the expression of cytotoxic molecules in ALK+ ALCL. Moreover, these findings demonstrate the expression of GzB and Perforin in this lymphoma is not solely due its presumed CTL origin, but that oncogenic signalling is actively influencing the expression of these proteins.
 ...
PMID:NPM-ALK and the JunB transcription factor regulate the expression of cytotoxic molecules in ALK-positive, anaplastic large cell lymphoma. 2132 8

NKL homeobox genes are basic regulators of cell and tissue differentiation, many acting as oncogenes in T-cell leukemia. Recently, we described an hematopoietic NKL-code comprising six particular NKL homeobox genes expressed in hematopoietic stem cells and lymphoid progenitors, unmasking their physiological roles in the development of these cell types. Hodgkin lymphoma (HL) is a B-cell malignancy showing aberrant activity of several developmental genes resulting in disturbed B-cell differentiation. To examine potential concordances in abnormal lymphoid differentiation of T- and B-cell malignancies we analyzed the expression of the hematopoietic NKL-code associated genes in HL, comprising HHEX, HLX, MSX1, NKX2-3, NKX3-1 and NKX6-3. Our approach revealed aberrant HLX activity in 8 % of classical HL patients and additionally in HL cell line L-540. Accordingly, to identify upstream regulators and downstream target genes of HLX we used L-540 cells as a model and performed chromosome and genome analyses, comparative expression profiling and functional assays via knockdown and overexpression experiments therein. These investigations excluded chromosomal rearrangements of the HLX locus at 1q41 and demonstrated that STAT3 operated directly as transcriptional activator of the HLX gene. Moreover, subcellular analyses showed highly enriched STAT3 protein in the nucleus of L-540 cells which underwent cytoplasmic translocation by repressing deacetylation. Finally, HLX inhibited transcription of B-cell differentiation factors MSX1, BCL11A and SPIB and of pro-apoptotic factor BCL2L11/BIM, thereby suppressing Etoposide-induced cell death. Collectively, we propose that aberrantly expressed NKL homeobox gene HLX is part of a pathological gene network in HL, driving deregulated B-cell differentiation and survival.
 ...
PMID:Aberrant expression of NKL homeobox gene HLX in Hodgkin lymphoma. 2958 48