Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA304643 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2968580_1.fastq.gz | Fastqsanger.gz | |||
| SRR2968580_2.fastq.gz | Fastqsanger.gz | |||
| SRR2968590_1.fastq.gz | Fastqsanger.gz | |||
| SRR2968590_2.fastq.gz | Fastqsanger.gz | |||
| SRR2968581_1.fastq.gz | Fastqsanger.gz |
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Project description:Transforming growth factor-β (TGF-β) signaling and microRNAs (miRNAs) are important gene regulatory components in cancer. Usually in advanced malignant stages, TGF-β signaling is elevated, but global miRNA expression is suppressed. Such a gene expression signature is well illustrated in a fibrosis/mesenchymal subtype of ovarian cancer (OC) that is of poor prognosis. However, the interplay between the two pathways in the OC subtype has not yet been elucidated. nc886 is a recently identified non-coding RNA implicated in several malignancies. nc886's high expression is associated with the poor prognosis of 285 patients in an OC cohort. Herein we have found in OC that nc886 expression is induced by TGF-β and that nc886 binds to the enzyme Dicer to inhibit the processing of miRNA precursors into mature forms. By preventing the miRNA pathway, nc886 emulates TGF-β in gene expression patterns and potentiates cell adhesion, migration, invasion, and drug resistance. We report nc886 as a novel molecular link between the TGF-β and miRNA pathways.
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Project description:Pedro Vizán, Daniel S. J. Miller, Ilaria Gori, Debipriya Das, Bernhard Schmierer & Caroline S. Hill. Controlling long-term signaling: receptor dynamics determine attenuation and refractory behavior of the TGF-β pathway. Science Signaling 6, 305 (2013).
Understanding the complex dynamics of growth factor signaling requires both mechanistic and kinetic information. Although signaling dynamics have been studied for pathways downstream of receptor tyrosine kinases and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, they have not been investigated for the transforming growth factor-β (TGF-β) superfamily pathways. Using an integrative experimental and mathematical modeling approach, we dissected the dynamic behavior of the TGF-β to Smad pathway, which is mediated by type I and type II receptor serine/threonine kinases, in response to acute, chronic, and repeated ligand stimulations. TGF-β exposure produced a transient response that attenuated over time, resulting in desensitized cells that were refractory to further acute stimulation. This loss of signaling competence depended on ligand binding, but not on receptor activity, and was restored only after the ligand had been depleted. Furthermore, TGF-β binding triggered the rapid depletion of signaling-competent receptors from the cell surface, with the type I and type II receptors exhibiting different degradation and trafficking kinetics. A computational model of TGF-β signal transduction from the membrane to the nucleus that incorporates our experimental findings predicts that autocrine signaling, such as that associated with tumorigenesis, severely compromises the TGF-β response, which we confirmed experimentally. Thus, we have shown that the long-term signaling behavior of the TGF-β pathway is determined by receptor dynamics, does not require TGF-β-induced gene expression, and influences context-dependent responses in vivo.
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