Brn-3a neuronal transcription factor functional expression in human prostate cancer

Diss, James K.J.; Faulkes, David J.; Walker, Marjorie M.; Patel, Alpesh; Foster, Christopher S.; Budhram-Mahadeo, Vishwanie; Djamgoz, Mustafa B.A.; Latchman, David S.

doi:10.1038/sj.pcan.4500837

Cited by 26 publications

(32 citation statements)

References 49 publications

(79 reference statements)

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“…These hypotheses have been supported by the recent findings of Diss et al [85,86] . They found that a neuronal transcription factor (Brn-3a) (overexpressed in aggressive NE tumors and in advanced PCa) controls a voltage-gated sodium channel (Nav 1.7) expression in human PCa (upregulation).…”

Section: Biogenic Polyamine Pathways and Neurotransmitterssupporting

confidence: 80%

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Neuroendocrine Differentiation in Prostate Cancer: From Lab to Bedside

et al. 2007

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Objectives: To discuss the current knowledge on induction, production, sustenance and promotion of neuroendocrine differentiation in human prostate cancer. Methods: Review of the literature using PubMed search and scientific journal publications. Results: Morphological evidence explains some functional relationship between neuroendocrine and neoplastic surrounding cells. Transdifferentiation phenomenon and new biochemical pathways could be included in the development of androgen independence and prostate cancer progression. Conclusion: Multiple evidence seems to confirm that a synergistic functional network between epithelial PSA secretory cells and neuroendocrine intraprostatic system is the main trigger for the induction and sustenance of neuroendocrine differentiation. The development of new antineoplastic molecules should consider the multiple interference of the intercellular network.

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Section: Biogenic Polyamine Pathways and Neurotransmitterssupporting

confidence: 80%

“…These androgen-independent neoplastic cells are able to increase the proliferation index (by increasing the Ki-67 positivity) of surrounding non-NE-phenotype cancer cells by the secretion of NE products through a paracrine mechanism (through transactivation of the androgen receptor) [18,75,76] .…”

Section: Autocrine/paracrine Interactionsmentioning

confidence: 99%

Neuroendocrine Differentiation in Prostate Cancer: From Lab to Bedside

et al. 2007

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“…Generation of cDNA and RT-PCR was performed as described (40). See SI Materials and Methods for details.…”

Section: Methodsmentioning

confidence: 99%

Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment

Nistala

Adams

Cambrook

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

378

356

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In several murine models of autoimmune arthritis, Th17 cells are the dominant initiators of inflammation. In human arthritis the majority of IL-17–secreting cells within the joint express a cytokine phenotype intermediate between Th17 and Th1. Here we show that Th17/1 cells from the joints of children with inflammatory arthritis express high levels of both Th17 and Th1 lineage-specific transcription factors, RORC2 and T-bet. Modeling the generation of Th17/1 in vitro, we show that Th17 cells “convert” to Th17/1 under conditions that mimic the disease site, namely low TGFβ and high IL-12 levels, whereas Th1 cells cannot convert to Th17. Th17/1 cells from the inflamed joint share T-cell receptor (TCR) clonality with Th17 cells, suggesting a shared clonal origin between Th17 and Th17/1 cells in arthritis. Using CD161, a lectin-like receptor that is a marker of human Th17, we show synovial Th17 and Th17/1 cells, and unexpectedly, a large proportion of Th1 cells express CD161. We provide evidence to support a Th17 origin for Th1 cells expressing CD161. In vitro, Th17 cells that convert to a Th1 phenotype maintain CD161 expression. In the joint CD161+ Th1 cells share features with Th17 cells, with shared TCR clonality, expression of RORC2 and CCR6 and response to IL-23, although they are IL-17 negative. We propose that the Th17 phenotype may be unstable and that Th17 cells may convert to Th17/1 and Th1 cells in human arthritis. Therefore therapies targeting the induction of Th17 cells could also attenuate Th17/1 and Th1 effector populations within the inflamed joint.

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“…At later stages, the disease becomes refractory to androgen ablation; however, curiously, knockdown of AR is still sufficient to inhibit the growth of androgen-independent cancers, indicating that although androgens may no longer be required, AR remains critical for survival (52,53). Intriguingly, relative to agematched controls, Brn-3a expression is elevated in prostate cancer tissue, and its expression increases with disease progression (54). Thus, in light of the interaction between Brn-3a and AR described in this work, it may be the case that late stage prostate cancers are able to use Brn-3a to increase activation of AR-regulated genes, thereby reducing the requirement for androgens.…”

Section: Discussionmentioning

confidence: 95%

A Simple Technique for the Prediction of Interacting Proteins Reveals a Direct Brn-3a-Androgen Receptor Interaction

Berwick

Diss

Budhram-Mahadeo

et al. 2010

Journal of Biological Chemistry

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The formation of multiprotein complexes constitutes a key step in determining the function of any translated gene product. Thus, the elucidation of interacting partners for a protein of interest is of fundamental importance to cell biology. Here we describe a simple methodology for the prediction of novel interactors. We have applied this to the developmental transcription factor Brn-3a to predict and verify a novel interaction between Brn-3a and the androgen receptor (AR). We demonstrate that these transcription factors form complexes within the nucleus of ND7 neuroblastoma cells, while in vitro pull-down assays show direct association. As a functional consequence of the Brn3a-AR interaction, the factors bind cooperatively to multiple elements within the promoter of the voltage-gated sodium channel, Nav1.7, leading to a synergistic increase in its expression. Thus, these data define AR as a direct Brn-3a interactor and verify a simple interacting protein prediction methodology that is likely to be useful for many other proteins.Although the importance of protein-protein interaction is long established, the rise of postgenomic technologies, in particular interactomics in yeast (1), and the growing popularity of systems biology (2) have served to highlight the importance of protein complexes to cell biology. For example, in the field of transcriptional regulation, the discovery of cis-regulatory elements vast distances from the transcriptional start site of a gene requires the formation of protein complexes to bridge often huge expanses of genomic DNA (3). In addition, the concept of promoters and cis-regulatory elements as "coincidence detectors" that integrate and process a diversity of inputs into a decision on the expression of a gene requires the construction of complex molecular machinery to perform these tasks (4). Although the need to study multiprotein complexes in basic research is clear, its relevance to applied disciplines should not be underestimated. In the case of transcriptional complexes, there is a growing body of data supporting the idea that interactions between transcription factors and between transcription factors and co-factors constitute a potent target for therapeutic intervention (5-7). In addition to molecules that block or disrupt protein-protein interactions, the creation of drugs that stabilize a transcriptional complex has been postulated (6), thus suggesting the possibility that, by modulating protein binding events, genes critical to pathological processes may be switched on or off pharmacologically.The Brn-3a transcription factor (also known as Pou4F1) is a class IV POU (Pit-Oct-Unc) family transcription factor. It is expressed at high levels in the sensory neurons of the trigeminal ganglia and dorsal root ganglia (DRG) 2 and in specific structures of the brain (8). Brn-3a is indispensable for normal development because Brn-3a knock-out mice display a severe depletion of sensory neurons. Presumably grossly impaired in nociception and proprioception, these animals are unable to...

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Brn-3a neuronal transcription factor functional expression in human prostate cancer

Cited by 26 publications

References 49 publications

Neuroendocrine Differentiation in Prostate Cancer: From Lab to Bedside

Neuroendocrine Differentiation in Prostate Cancer: From Lab to Bedside

Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment

A Simple Technique for the Prediction of Interacting Proteins Reveals a Direct Brn-3a-Androgen Receptor Interaction

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