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ETV2 regulates PARP-1 binding protein to induce ER stress-mediated cell death in tuberin-deficient cells

ABSTRACT: Syk inhibitor demonstrates antiproliferative effect on Tsc2-deficient cells and LAM lung nodules similar to rapamycin. A feedback loop between Syk inhibition and mTORC1 inhibition pathways is also present in these Tsc2-deficient cells. We used microarrays to discern the potential difference in Syk inhibition and mTORC1-inhibition pathways. The goal was to investigate regulatory pathways or targets of Syk inhibition to induce cytocidal response in Tsc2-deficient cells, independent of its crosstalk with mTORC1 signaling.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183110 | GEO | 2022/02/14

REPOSITORIES: GEO

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Effect of the reduced mTORC1 activity on gene expression in LAM cells

Project description:mTORC1 is inhibited by rapamycin or Torin1 in lymphangioleiomyomatosis (LAM) 621-101 (TSC2-deficient) cells, in which mTORC1 activity is elevated, and we compared these effects to inhibition of S6K and its target SRPK2.

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Identification of Tfeb-dependent genes downstream of mTORC1 in MEFs

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Project description:Lymphangioleiomyomatosis (LAM) is a rare, debilitating lung disease that predominantly affects women of reproductive age. LAM cells carry deleterious mutations of tuberous sclerosis complex (TSC1/TSC2) genes, resulting in hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) and ultimately dysregulated cell growth. The integrative single cell omics data identified the activation of uterine specific HOX-PBX transcriptional programming in pulmonary LAMCORE cells. Network analysis predicted homeobox transcription factors including PBX1 and HOXD11 as key regulators controlling LAMCORE cell fate. Targeting the HOX-PBX network may have therapeutic value in LAM and TSC-related diseases, and possibly in other mTORC1-hyperactive neoplasms.

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Integrative Single Cell Multiomic Profiling Analysis Reveals HOX-PBX Gene Regulatory Network Regulating the Survival of mTOR Hyperactive Cells [snATAC-Seq]

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Rapamycin-insensitive up-regulation of MMP2 and other genes in TSC2- deficient LAM-like cells

Project description:Rationale: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of lymphangioleiomyomatosis (LAM). Objectives: To investigate how TSC1 or TSC2 deficiency alters MMP expression and regulation. Methods: We studied immortalized cells that lack TSC2 derived from an angiomyolipoma (AML) of a LAM patient, and a TSC2 add back derivative; and murine embryonic fibroblast cells that lack Tsc1 or Tsc2 and respective controls. Global gene expression analysis was carried out in the AML and derivative cell lines. MMP levels in the conditioned media from these cells were analyzed by zymography and ELISA. Measurements and Main Results: We found increased MMP-2 expression in cells lacking TSC1/TSC2 compared to their respective controls by zymography. MMP-2 overproduction by these cells was not affected by rapamycin treatment. Gene expression analysis confirmed increased MMP-2 gene expression that was not affected by rapamycin. Furthermore, multiple other genes were found to be over-expressed in rapamycin-treated TSC2-deficient cells compared to TSC2+ cells. Conclusions: We conclude that TSC1/TSC2 deficiency leads to MMP-2 overproduction that is rapamycin insensitive, and that several genes exhibit similar patterns suggesting TSC1/TSC2 dependent but mTOR independent pathways may be involved in the pathogenesis of LAM.

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