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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

ABSTRACT: The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

PROVIDER: PRJNA476979 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7405200.fastq.gz	Fastqsanger.gz
	SRR7405201.fastq.gz	Fastqsanger.gz
	SRR7405202.fastq.gz	Fastqsanger.gz
	SRR7405203.fastq.gz	Fastqsanger.gz
	SRR7405204.fastq.gz	Fastqsanger.gz

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Project description:The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

Project description:The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [ribosome profiling]

Project description:The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non-neuroendocrine androgen receptor-low castration resistant prostate cancer (AR low CRPC) is increasing in occurrence amongst patients and is uniformly fatal. The mechanisms that promote this phenotype remain poorly understood. Through molecular studies of murine and human models of AR low CRPC, we have identified a new functional interface between the androgen receptor and the translation initiation complex inhibitor 4EBP1. AR directly regulates 4EBP1 expression which translationally represses eIF4F complex formation and a pro-proliferation program. In the context of AR low prostate cancer, de-repression of translation initiation drives the aberrant expression of the pro-proliferation regulon which fuels uncontrolled cell growth. Genetic and pharmacologic inhibition of the downstream eIF4F translation initiation complex reverses the proliferation phenotype in vitro and in vivo. These findings reveal a new previously unrecognized druggable nexus which functionally link the processes of mRNA transcription and translation initiation in a rapidly emerging class of advanced lethal prostate cancer

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer [RNA-seq]

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer.

Project description:The androgen receptor (AR) is a driver of cellular differentiation and prostate cancer development. An extensive body of work has linked these normal and aberrant cellular processes to mRNA transcription; however, the extent to which AR regulates posttranscriptional gene regulation remains unknown. Here, we demonstrate that AR uses the translation machinery to shape the cellular proteome. We show that AR is a negative regulator of protein synthesis and identify an unexpected relationship between AR and the process of translation initiation in vivo. This is mediated through direct transcriptional control of the translation inhibitor 4EBP1. We demonstrate that lowering AR abundance increases the assembly of the eIF4F translation initiation complex, which drives enhanced tumor cell proliferation. Furthermore, we uncover a network of pro-proliferation mRNAs characterized by a guanine-rich cis-regulatory element that is particularly sensitive to eIF4F hyperactivity. Using both genetic and pharmacologic methods, we demonstrate that dissociation of the eIF4F complex reverses the proliferation program, resulting in decreased tumor growth and improved survival in preclinical models. Our findings reveal a druggable nexus that functionally links the processes of mRNA transcription and translation initiation in an emerging class of lethal AR-deficient prostate cancer.

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The androgen receptor regulates a druggable translational regulon in advanced prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-07-31 | GSE116083 | GEO

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Project description:The rate of protein synthesis varies according to the mRNA sequence in ways that affect gene expression. Global analysis of translational pausing is now possible with ribosome profiling. Here, we revisit an earlier report that Shine-Dalgarno sequences are the major determinant of translational pausing in bacteria. Using refinements in the profiling method as well as biochemical assays, we find that SD motifs have little (if any) effect on elongation rates. We argue that earlier evidence of pausing arose from two factors. First, in previous analyses, pauses at Gly codons were difficult to distinguish from pauses at SD motifs. Second, and more importantly, the initial study preferentially isolated long ribosome-protected mRNA fragments that are enriched in SD motifs. These findings clarify the landscape of translational pausing in bacteria as observed by ribosome profiling. Ribosome profiling (three replicates) and RNAseq (two replicates) of E. coli MG1655

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Genome-wide translational analysis of RAW264 macrophages by ribosome profiling

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