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Non-canonical mTORC1-TFEB activation due to loss of TSC1 determines hepatocyte plasticity and drives cholangiocarcinogenesis

ABSTRACT: The aim of the study is to investigate the role and mechanisms of tuberous sclerosis complex 1 (TSC1) and TFEB in liver cancer study。Hepatic mRNA profiles of WT , hepatic TSC1 KO mice and hepatic TSC1 and TFEB DKO mouse liver

ORGANISM(S): Mus musculus

PROVIDER: GSE318879 | GEO | 2026/07/17

REPOSITORIES: GEO

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Persistent mTORC1 activation due to loss of liver tuberous sclerosis complex 1 promotes liver injury in alcoholic hepatitis.

Project description:The aim of the study is to investigate the role and mechanisms of tuberous sclerosis complex 1 (TSC1) and mechanistic target of rapamycin complex 1 (mTORC1) in alcohol associated liver disease Hepatic RNA profiles of WT and hepatic TSC1 KO mice fed with alcohol or control diet using Gao binge alcohol model.

2023-04-25 | GSE230175 | GEO

TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex

Project description:Tuberous Sclerosis Complex (TSC) is caused by germline TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs including the brain, heart, lung (lymphangioleiomyomatosis), and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in models of TSC. To determine the impact of TFEB in vivo, we generated two novel mouse models of TSC, resulting in premature death, in which kidney pathology was the primary phenotype. RNA sequencing revealed that lysosomal and proteasomal gene pathways were the most highly upregulated in the TSC2-deficient kidneys. Knockout of TFEB rescued both kidney pathology and overall survival in both models, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, mTORC1 activity, which was elevated in the TSC2 knockout kidneys, was normalized by TFEB knockout. Knockdown of Rheb or treatment of TSC2-deficient cells with Rapamycin paradoxically increases TFEB phosphorylation at the mTORC1-site (S211) and relocalizes TFEB from the nucleus to the cytoplasm via a Rag-dependent mechanism. Accordingly, treatment of TSC2 knockout mice with Rapamycin normalized lysosomal gene expression, similar to TFEB knockout, suggesting that the beneficial effects of Rapamycin in TSC are TFEB-dependent. These results change the view of the mechanisms leading to mTORC1 hyperactivation in TSC and may lead to novel therapeutic avenues for the treatment of TSC.

2023-09-28 | GSE244072 | GEO

Hepatic transcriptome phenotypes after mTORC1 activation through Tsc1 and Depdc5 mutations

Project description:We report RNA-seq results from liver tissues of control mice, liver-specific Tsc1 knockout mice, liver-specific Depdc5 knockout mice and liver-specific Tsc1/Depdc5 double knockout mice.

2020-04-14 | GSE136684 | GEO

Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy

Project description:The purpose of this study is to identify the differential transcriptome profiles in WT, hepatic Atg5 KO, TSC1 KO, Atg5/TSC1 DKO, Atg5/TSC1/p62 TKO and Atg5/TSC1/Nrf2 TKO mouse livers. Hepatic mRNA from 2-month-old mice from 5 different mouse strains were extracted and performed for Nextseq analysis in quadruplicates.

2021-12-14 | GSE186783 | GEO

Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).

2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress

Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice

2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress

Comparison of the kidney transcriptome of 45 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre), 45 days old principal cell-specific Tsc1 knockout/Foxi1 knockout (Tsc1/Foxi1 dKO), and 45 days old WT mice

Project description:Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. The transcription factor FOXI1 is indispensable in the development of intercalated cells. The expression of Foxi1 mRNA is significantly upregulated in the kidneys of various mouse models of TSC. The simultaneous ablation of Tsc1 and Foxi1 prevents the formation of cysts in the kidneys of Tsc1 KO mice. In these studies, we compared the renal transcriptomes of 45 days old principal cell-specific Tsc1 knockout, Tsc1/Foxi1 double knockout, and WT mice.

2026-02-18 | GSE311307 | GEO

Drosophila S2R+ / TSC1 / TSC2 mutant phosphoproteomics

Project description:The tuberous sclerosis complex (TSC) family of tumor suppressors, TSC1 and TSC2, function together in an evolutionarily conserved protein complex that is a point of convergence for major cell signaling pathways that regulate mTOR complex 1 (mTORC1). Mutation or aberrant inhibition of the TSC complex is common in various human tumor syndromes and cancers. The discovery of novel therapeutic strategies to selectively target cells with functional loss of this complex is therefore of substantial clinical relevance to TSC and sporadic cancers. We developed a CRISPR-based method to generate homogenous mutant Drosophila cell lines. By combining TSC1 and TSC2 mutant cell lines with RNAi screens against all kinases and phosphatases, we identified synthetic interactions with TSC1 and TSC2. Knockdown of three candidate genes (mRNA-cap, Pitslre and CycT; orthologs of RNGTT, CDK11 and CCNT1 in humans) reduced the population growth rate of both Drosophila TSC1 and TSC2 mutant cells but not that of wild-type cells. Moreover, knockdown of all three genes displayed similar selective effects in mammalian TSC2-deficient cell lines, including human tumor-derived cells, illustrating the power of this cross species screening strategy to identify potential drug targets.

2018-10-24 | PXD002670 | Pride

Identification of Tfeb-dependent genes downstream of mTORC1 in MEFs

Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-bM-^@M-^\low/low/high/lowM-bM-^@M-^] or M-bM-^@M-^\LLHLM-bM-^@M-^]. We found that mTORC1 regulated the expression of, among other lysosomal genes, V-ATPases through the transcription factor EB (TFEB, Tcfeb in the mouse). The knockdown of Tfeb resulted in the 'flattening' of the LLHL pattern and allowed the identification of genes regulated by mTORC1 through Tfeb Mouse embryo fibroblasts (MEFs) wild type or deficient in Tsc2 expressing a Tfeb shRNA or scrambled shRNA vector were treated with 25 nM rapamycin or vehicle (methanol) for 24 h under low serum conditions (0.1% FBS)

2011-08-02 | E-GEOD-28021 | biostudies-arrayexpress