Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B-MYB is a ubiquitously expressed transcription factor involved in the regulation of cell survival, proliferation, and differentiation. In an attempt to isolate B-MYB-regulated genes that may explain the role of B-MYB in cellular processes, representational difference analysis was performed in neuroblastoma cell lines with different levels of B-MYB expression. One of the genes, the mRNA levels of which were enhanced in B-MYB expressing cells, was ApoJ/Clusterin(SGP-2/TRMP-2) (ApoJ/Clusterin), previously implicated in regulation of apoptosis and tumor progression. Here we show that the human ApoJ/Clusterin gene contains a Myb binding site in its 5' flanking region, which interacts with bacterially synthesized B-MYB protein and mediates B-MYB-dependent transactivation of the ApoJ/Clusterin promoter in transient transfection assays. Endogenous ApoJ/Clusterin expression is induced in mammalian cell lines following transient transfection of a B-MYB cDNA. Blockage of secreted clusterin by a monoclonal antibody results in increased apoptosis of neuroblastoma cells exposed to the chemotherapeutic drug doxorubicin. Thus, activation of ApoJ/Clusterin by B-MYB may be an important step in the regulation of apoptosis in normal and diseased cells.
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PMID:Direct transactivation of the anti-apoptotic gene apolipoprotein J (clusterin) by B-MYB. 1077 Sep 37

By using the yeast two-hybrid system, the zinc finger protein ZPR9 was identified as one of the B-MYB interacting proteins that associates with the carboxyl-terminal conserved region of B-MYB. ZPR9 was found to form in vivo complexes with B-MYB, as demonstrated by in vivo binding assay and coimmunoprecipitation experiments of the endogenously and exogenously expressed proteins. Deletion analysis revealed that this binding was mediated by all three functional domains, an amino-terminal DNA-binding domain, a transactivation domain, and a carboxyl-terminal conserved region of B-MYB. We show that the interaction of ZPR9 with B-MYB is functional because cotransfection of ZPR9 significantly up-regulates B-MYB transcriptional activity in a dose-dependent manner. In addition, coexpression of ZPR9 with B-MYB caused the accumulation of B-MYB, as well as ZPR9, in the nucleus. Furthermore, constitutive expression of ZPR9 in human neuroblastoma cells induces apoptosis in the presence of retinoic acid. These results strongly suggest that ZPR9 plays an important role in modulation of the transactivation by B-MYB and cellular growth of neuroblastoma cells.
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PMID:Enhancement of B-MYB transcriptional activity by ZPR9, a novel zinc finger protein. 1264 66

B-MYB is an oncoprotein highly expressed and frequently amplified in human neoplasia. B-MYB is more expressed in neuroblastoma patients with adverse prognostic indicators, corroborating the hypothesis that it plays an important role in this pediatric malignancy. While attempting targeting strategies for therapeutic purposes, we found that the B-MYB protein was difficult to downregulate in neuroblastoma cells using siRNA approaches. This lead us to discover that the B-MYB protein half-life is increased in neuroblastoma compared to other normal or transformed human cell lines. The B-MYB protein is quickly destroyed and apoptosis is induced in Ewing sarcoma cells exposed to UV irradiation. In contrast, neuroblastoma cells are resistant to UV-induced apoptosis and B-MYB protein levels do not change in UV-treated cells. In further experiments, we show that the B-MYB protein extracted from neuroblastoma cells is hypophosphorylated. It was previously shown that B-MYB phosphorylation activates its transcriptional activity but also promotes its destruction. Overexpression of a non-phosphorylatable B-MYB mutant protects cells from UV-induced apoptosis, suggesting that its reduced phosphorylation, rather than causing its inactivation, facilitates B-MYB pro-survival activity. Thus, expression of stable, hypophosphorylated B-MYB in neuroblastoma may promote cell survival and induce aggressive tumour growth.
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PMID:B-MYB is hypophosphorylated and resistant to degradation in neuroblastoma: implications for cell survival. 1758 87

MYCN is a member of the MYC family of oncoproteins frequently amplified or overexpressed in aggressive, paediatric tumours of the nervous system. In this study we have identified the gene B-MYB, encoding the transcription factor also known as MYBL2, as a downstream target of MYCN. Using multiple in silico databases we show that expression of B-MYB significantly correlates with that of MYCN in neuroblastoma patients. MYCN binds to and activates the B-MYB gene in vivo and in vitro. Blunting B-MYB expression by RNA interference causes reduced proliferation of MYCN amplified, but not MYCN-non amplified, neuroblastoma cell lines, indicating that tumour cells are addicted to B-MYB in a MYCN dependent manner. Notably, B-MYB binds in vivo to the MYCN amplicon and is required for its expression. We conclude that MYCN and B-MYB are engaged in a reciprocal regulatory loop whose pharmacological targeting could be beneficial to patients with the aggressive forms of cancer in which MYCN is amplified.
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PMID:Addiction of MYCN amplified tumours to B-MYB underscores a reciprocal regulatory loop. 2130 74

The transcription factor MycN is the prototypical neuroblastoma oncogene and a potential therapeutic target. However, its strong expression caused by gene amplification in about 30% of neuroblastoma patients is a considerable obstacle to the development of therapeutic approaches aiming at eliminating its tumourigenic activity. We have previously reported that B-Myb is essentially required for transcription of the MYCN amplicon and have also shown that B-MYB and MYCN are engaged in a feed forward loop promoting the survival/proliferation of neuroblastoma cells. We postulated that pharmacological strategies breaking the B-MYB/MYCN axis should result in clinically desirable effects. Thus, we implemented a high throughput chemical screen, using a curated library of ~1500 compounds from the National Cancer Institute, whose endpoint was the identification of small molecules that inhibited B-Myb. At the end of the screening, we found that the compounds pinafide, ellipticine and camptothecin inhibited B-Myb transcriptional activity in luciferase assays. One of the compounds, the topoisomerase-1 inhibitor camptothecin, is of considerable clinical interest since its derivatives topotecan and irinotecan are currently used as first and second line treatment agents for various types of cancer, including neuroblastoma. We found that neuroblastoma cells with amplification of MYCN are more sensitive than MYCN negative cells to camptothecin and topotecan killing. Campothecin and topotecan caused selective down-regulation of B-Myb and MycN expression in neuroblastoma cells. Notably, forced overexpression of B-Myb could antagonize the killing effect of topotecan and camptothecin, demonstrating that the transcription factor is a key target of the drugs. These results suggest that camptothecin and its analogues should be more effective in patients whose tumours feature amplification of MYCN and/or overexpression of B-MYB.
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PMID:A chemical screen identifies the chemotherapeutic drug topotecan as a specific inhibitor of the B-MYB/MYCN axis in neuroblastoma. 2261 21

MEIS2 has an important role in development and organogenesis, and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. Here, we show that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M-phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell-cycle genes, including those required for DNA replication, G2-M checkpoint control and M-phase progression. Importantly, we identify MEIS2 as a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of cell-cycle gene expression. Further, we show that FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. These findings link a developmentally important gene to the control of cell proliferation and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is frequently observed in cancers of poor prognosis.
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PMID:MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression. 2521 Aug