Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Cytoplasmic Accumulation of Incompletely Glycosylated Sex Hormone-binding Globulin (SHBG) Enhances Androgen Action in Proximal Convoluted Tubule Epithelial Cells

ABSTRACT: Identification of androgen-responsive genes that are influenced by the presence of a functional SHBG versus a steroid-binding-deficient SHBG mutant (SHBG S42L) in the cytoplasm of PCT cells. The hypothesis tested in the study was that SHBG enhances androgen action. Results provide important information that intracellular SHBG enhances androgen-dependent stimulation or repression in PCT cells. RNA was extracted for gene expression profiling from PCT cells expressing wild-type human SHBG or the human SHBG S42L mutant after treatment with testosterone or DHT, and hybridized to Illumina Mouse WG-6 v2.0 expression bead chips. Three replicates each.

ORGANISM(S): Mus musculus

SUBMITTER: Geoffrey Hammond

PROVIDER: E-GEOD-26058 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (~25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (~23%), five events involved transcripts derived from known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of the alternative TSC2 mRNA isoform was directly regulated by androgens. Furthermore, by chromatin immunoprecipitation, we observed recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa. Total 8 samples were analysed. 4 control (LNCaP cells grown in RPMI-1640 media with charcoal-stripped 10% FBS devoid of steroids) and 4 treatment (LNCaP cells grown in media devoid of steroid, and subsequently treated with 10nM R1881 synthetic androgen analogue for 24 hours).

Dataset Information

Cytoplasmic Accumulation of Incompletely Glycosylated Sex Hormone-binding Globulin (SHBG) Enhances Androgen Action in Proximal Convoluted Tubule Epithelial Cells

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