Dataset Information

RNAseq of 4T1 cells expressing exogenous LINC01133

ABSTRACT: The PI3K pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ~15% of breast cancers with no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC owing largely to still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long non-coding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC, and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted pro-tumorigenic roles in TNBC, and that it governed a previously undescribed mTORC2-dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, we show that LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative mRNA regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth and we show that the LINC01133-PROTOR1/PRR5 pathway tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA-based theranostic in clinical TNBC management. We performed comparative gene expression profiling analyses using RNA-seq of triplicates of control 4T1 cells (harboring empty plasmid control) and 4T1 cell trioplicates expressing exogenous LINC01133.

ORGANISM(S): Mus musculus

PROVIDER: GSE212004 | GEO | 2022/10/03

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:DallePezze2012 - TSC-independent mTORC2 regulation This model is described in the article: A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K. Sci Signal 2012 Mar; 5(217): ra25 Abstract: The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2. By analyzing the effects of perturbations targeting several levels within the network in silico and experimentally, we found that, in contrast to current hypotheses, the TSC1-TSC2 complex was not a direct or indirect (acting through the negative feedback loop) regulator of mTORC2. Although mTORC2 activation required active PI3K, this was not affected by the negative feedback loop. Therefore, we propose an mTORC2 activation pathway through a PI3K variant that is insensitive to the negative feedback loop that regulates mTORC1. This putative pathway predicts that mTORC2 would be refractory to Akt, which inhibits TSC1-TSC2, and, indeed, we found that mTORC2 was insensitive to constitutive Akt activation in several cell types. Our results suggest that a previously unknown network structure connects mTORC2 to its upstream cues and clarifies which molecular connectors contribute to mTORC2 activation. This model is hosted on BioModels Database and identified by: BIOMD0000000581. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

RNAseq of 4T1 cells expressing exogenous LINC01133

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets