A Splicing Variant of the Androgen Receptor Detected in a Metastatic Prostate Cancer Exhibits Exclusively Cytoplasmic Actions

Jagla, Monika; Fève, Marie; Kessler, Pascal; Lapouge, Gaëlle; Erdmann, Eva; Serra, Sébastian; Bergerat, Jean‐Pierre; Céraline, Jocelyn

doi:10.1210/en.2007-0446

Cited by 62 publications

(64 citation statements)

References 45 publications

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“…When these four cell lines were compared using miRNA microarray analyses, mir-184, mir-361, and mir-424 were significantly up-regulated, and mir-19b, mir-29b, mir128b, mir-146a, mir-146b, mir-221, mir-222, and mir-663 were down-regulated in HRPC-related LNCaP C4-2B and PC3 cells as compared to androgen-dependent LNCaP and PC3-AR9 cells. Only mir-184 has been proposed to possess oncogenic activities in prostate cancer (Jagla et al 2007). A recent study demonstrated that an aberrant splicing variant of androgen receptor, AR23, contained 69 nt of the intron 2 sequence, which separated the two AR zinc fingers required for nuclear entry (Jagla et al 2007).…”

Section: Resultsmentioning

confidence: 99%

Loss of mir-146a function in hormone-refractory prostate cancer

Lin¹,

Chiang²,

Chang³

et al. 2008

RNA

356

249

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The pattern of microRNA (miRNA) expression is associated with the degree of tumor cell differentiation in human prostate cancer. MiRNAs bind complementarily to either oncogenes or tumor suppressor genes, which are consequently silenced, resulting in alterations of tumorigenecity. We have detected eight down-regulated and three up-regulated known miRNAs in androgen-independent human prostate cancer cells compared to those in androgen-dependent cells, using miRNA microarray analyses. These identified miRNAs showed the same expression patterns in hormone-refractory prostate carcinomas (HRPC) compared to androgen-sensitive noncancerous prostate epithelium as determined by fluorescent in situ hybridization assays in human prostate cancer tissue arrays. One of the eight down-regulated miRNAs, mir-146a, was selected and constitutively expressed to examine its effects on suppression of prostate cancer transformation from androgen-dependent to -independent cells as determined by in vitro tumorigenecity assays. Transfection of mir-146a, which perpetually express the miRNA, suppressed >82% of the expression of the targeted protein-coding gene, ROCK1, in androgen-independent PC3 cells, consequently markedly reducing cell proliferation, invasion, and metastasis to human bone marrow endothelial cell monolayers. Given that ROCK1 is one of the key kinases for the activation of hyaluronan (HA)-mediated HRPC transformation in vivo and in PC3 cells, mir-146a may function as a tumor-suppressor gene in modulating HA/ROCK1-mediated tumorigenecity in androgen-dependent prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Loss of mir-146a function in hormone-refractory prostate cancer

Lin¹,

Chiang²,

Chang³

et al. 2008

RNA

356

249

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“…This variant results from aberrant splicing of intron 2, resulting in the insertion of 23-amino acids between the two zinc-fingers of the DNA-binding domain. This AR-variant is exclusively localized in the cytoplasm (34). AR recognizes and binds to respective responsive elements (ARE) representing two hexameric direct repeats (AGAACA) separated by a three nucleotide spacer, with the half site repeated on the same strand.…”

Section: Steroid and Thyroid Hormone Receptor Structurementioning

confidence: 99%

Steroid and thyroid hormone receptors in mitochondria

2008

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SummaryReceptors for glucocorticoids, estrogens, androgens, and thyroid hormones have been detected in mitochondria of various cell types by Western blotting, immunofluorescence labeling, confocal microscopy, and immunogold electron microscopy. A role of these receptors in mitochondrial transcription, OXPHOS biosynthesis, and apoptosis is now being revealed. Steroid and thyroid hormones regulate energy production, inducing nuclear and mitochondrial OXPHOS genes by way of cognate receptors. In addition to the action of the nuclearly localized receptors on nuclear OXPHOS gene transcription, a parallel direct action of the mitochondrially localized receptors on mitochondrial transcription has been demonstrated. The coordination of transcription activation in nuclei and mitochondria by the respective receptors is in part realized by their binding to common trans acting elements in the two genomes. Recent evidence points to a role of the mitochondrial receptors in cell survival and apoptosis, exerted by genomic and nongenomic mechanisms. The identification of additional receptors of the superfamily of nuclear receptors and of other nuclear transcription factors in mitochondria increases their arsenal of regulatory molecules and further underlines the central role of these organelles in the integration of growth, metabolic, and cell survival signals.2008 IUBMB IUBMB Life, 60(4): [210][211][212][213][214][215][216][217][218][219][220][221][222][223] 2008

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“…Importantly, cytoplasmic DHTactivated AR23 remains partially active, with the ability to activate transcription from androgen-responsive promoters. Such novel cytoplasmic actions for this splicing AR variant suggest possible contribution in PrC progression [29].…”

Section: Androgen Receptor Co-activators and Co-repressorsmentioning

confidence: 92%

“…One AR variant, AR23, results from AS of intron 2, in which the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain [29]. Upon ligand binding (dihydrotestosterone [DHT]), nuclear entry of AR23 is impaired.…”

Section: Androgen Receptor Co-activators and Co-repressorsmentioning

confidence: 99%

Alternative Splicing in Prostate and Breast Cancer

Watson¹,

Watson²

2010

TOCJ

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UAb stract: Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, thus contributing to proteomic diversity in higher eukaryotes. Multiple studies demonstrate that alternative splicing patterns are altered during cancer progression. Several different mechanisms can contribute to changes in the regulation of alternative splicing. This report will provide an overview of how splicing microarrays and large-scale sequencing are being used to identify splicing changes in breast and prostate cancer. Global analyses of splice variants have identified cancer-specific splice variant patterns that have potential use as biomarkers and potentially have prognostic value as well as may represent novel therapeutic targets. A description of specific splice variants with differential expression in these cancers and their possible functions will be presented.

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A Splicing Variant of the Androgen Receptor Detected in a Metastatic Prostate Cancer Exhibits Exclusively Cytoplasmic Actions

Cited by 62 publications

References 45 publications

Loss of mir-146a function in hormone-refractory prostate cancer

Loss of mir-146a function in hormone-refractory prostate cancer

Steroid and thyroid hormone receptors in mitochondria

Alternative Splicing in Prostate and Breast Cancer

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