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)

The Brn-3a and Brn-3b POU family transcription factors have previously been shown to have functionally antagonistic effects, with Brn-3a activating specific gene promoters which are repressed by Brn-3b. We show here that proliferating cell lines of human neuroblastoma origin have a high ratio of Brn-3b to Brn-3a compared with other cell lines derived from related tumours. Moreover, the level of Brn-3a rises and that of Brn-3b falls when neuroblastoma cell lines are exposed to treatments which induce a cessation of proliferation. Such treatments also result in the activation of a test promoter which is normally stimulated by Brn-3a and repressed by Brn-3b. Our findings suggest that these antagonistic factors may play a key role in regulation of gene expression during human neuroblastoma differentiation and could thus represent a potential therapeutic target for treatments designed to induce such differentiation.
 ...
PMID:The functionally antagonistic POU family transcription factors Brn-3a and Brn-3b show opposite changes in expression during the growth arrest and differentiation of human neuroblastoma cells. 878 54

Neuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.
 ...
PMID:The Brn-3b transcription factor regulates the growth, behavior, and invasiveness of human neuroblastoma cells in vitro and in vivo. 1497 Feb 34

The Brn-3b POU domain transcription factor is elevated in a significant proportion of breast cancers and in neuroblastoma tumours, where it is associated with increased proliferation, anchorage-independent growth, faster and larger tumour growth in xenograft models, resistance to growth inhibitory stimuli and increased migratory potential. These effects are associated with the ability of Brn-3b to regulate specific genes associated with these processes. Reducing Brn-3b can reverse many of these effects, suggesting that it may be possible to alter the growth and behaviour of tumour cells by abrogating Brn-3b in these cancers. This review discusses the effect of altering Brn-3b in these cancer cells and possible approaches to targeting Brn-3b as a strategy for therapy in treatment of breast cancers.
 ...
PMID:Targeting Brn-3b in breast cancer therapy. 1644 Dec 25

The Brn-3a and Brn-3b transcription factor have opposite and antagonistic effects in neuroblastoma cells since Brn-3a is associated with differentiation whilst Brn-3b enhances proliferation in these cells. In this study, we demonstrate that like Brn-3a, Brn-3b physically interacts with p53. However, whereas Brn-3a repressed p53 mediated Bax expression but cooperated with p53 to increase p21cip1/waf1, this study demonstrated that co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21cip1/waf1. Consequently co-expression of Brn-3b with p53 resulted in enhanced apoptosis, which is in contrast to the increased survival and differentiation, when Brn-3a is co-expressed with p53. For Brn-3b to cooperate with p53 on the Bax promoter, it requires binding sites that flank p53 sites on this promoter. Furthermore, neurons from Brn-3b knock-out (KO) mice were resistant to apoptosis and this correlated with reduced Bax expression upon induction of p53 in neurons lacking Brn-3b compared with controls. Thus, the ability of Brn-3b to interact with p53 and modulate Bax expression may demonstrate an important mechanism that helps to determine the fate of cells when p53 is induced.
 ...
PMID:Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression. 1714 18

The post-transcriptional control of mRNA levels is a very powerful mechanism which allows cells to quickly change the amount of specific proteins. In this study, we wanted to analyze whether the Brn-3b transcription factor, essential for the proper development of mouse retinal ganglion cells, is subjected to such post-transcriptional regulation. In particular, due to its conservation amongst different species, we wanted to study the role of its 3' untranslated region (3'UTR). We show that the 3'UTR of the Brn-3b mRNA does indeed contain regulatory sequences that mediate mRNA degradation upon serum starvation-induced differentiation of ND7 neuroblastoma cells. The specific region mediating this effect has been characterized and two different microRNAs that potentially regulate the stability of Brn-3b have been identified. Moreover we show that Dicer, one of the key enzymes in the production of microRNAs, is strongly up-regulated in ND7 cells subjected to differentiation.
 ...
PMID:Post-transcriptional regulation of the Brn-3b transcription factor in differentiating neuroblastoma cells. 1749 Jun 55

Brn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.
 ...
PMID:Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells. 1763 57

Brn-3a and Brn-3b are closely related members of the POU family of transcription factors which have opposite effects on the activity of target promoters. When mouse or human neuroblastoma cells are induced to differentiate to a non-dividing phenotype bearing numerous neuronal processes, the levels of Brn-3a rise dramatically whilst Brn-3b levels fall. Inhibition of Brn-3a expression using an antisense approach or over-expression of Brn-3b, prevents the differentiation of neuroblastoma cells in response to stimuli which normally induce it. Conversely, over-expression of Brn-3a induces differentiation in the absence of such stimuli. Hence the balance between Brn-3a and Brn-3b plays a key role in regulating neuroblastoma differentiation via the activation by Brn-3a or repression by Brn-3b of specific genes whose protein products are required for this process.
 ...
PMID:Regulation of neuroblastoma growth and differentiation by the POU family transcription factors Brn-3a and Brn-3b (Review). 2153 95