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The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

ABSTRACT: The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

PROVIDER: PRJNA434736 | ENA |

REPOSITORIES: ENA

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The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

Project description:Oncogenic signals can induce premature senescence (OIS) in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A sodium channel allowed cells to escape from OIS. Here we studied the transcriptome profiles of an OIS model based on human mammary epithelial cells stably expressing hTert to be immortalized and MEK:ER, a 4-hydroxytamoxifen (4-OHT) inducible oncogene MEK:ER (HEC-TM cells), to induce the oncogenic signal. We used an shRNA in order to knockdown SCN9A expression during OIS, and KCL treatment to study the impact of membrane depolarization on senescence induction. We showed that SCN9A and plama membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NFkB transcription factor, SCN9A expression, plasma membrane depolarization.

2018-02-21 | GSE110884 | GEO

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway.

Project description:Oncogenic signals lead to premature senescence in normal human cells causing a proliferation arrest and the elimination of these defective cells by immune cells. Oncogene-induced senescence (OIS) prevents aberrant cell division and tumor initiation. In order to identify new regulators of OIS, we performed a loss-of-function genetic screen and identified that the loss of SCN9A allowed cells to escape from OIS. The expression of this sodium channel increased in senescent cells during OIS. This upregulation was mediated by NF-?B transcription factors, which are well-known regulators of senescence. Importantly, the induction of SCN9A by an oncogenic signal or by p53 activation led to plasma membrane depolarization, which in turn, was able to induce premature senescence. Computational and experimental analyses revealed that SCN9A and plasma membrane depolarization mediated the repression of mitotic genes through a calcium/Rb/E2F pathway to promote senescence. Taken together, our work delineates a new pathway, which involves the NF-?B transcription factor, SCN9A expression, plasma membrane depolarization, increased calcium, the Rb/E2F pathway and mitotic gene repression in the regulation of senescence. This work thus provides new insight into the involvement of ion channels and plasma membrane potential in the control of senescence.

| S-EPMC5946064 | biostudies-literature

Time-resolved proteomic analysis of plasma membrane damage-dependent senescence

Project description:Plasma membrane damage-dependent senescence is a novel senescence subtype. Here, we compare the time-resolved proteomic profiles of plasma membrane damage-dependent senescence, DNA damage-dependent senescence, and replicative senescence to find the major differences between the senescence subtypes.

2024-12-20 | PXD047976 | JPOST Repository

IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis

Project description:Cytosolic dsDNA surveillance by cGAS-STING signaling triggers autophagy, biased mRNA translation, cellular senescence, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that IRF3, activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a well-known tumor suppressor and key cell cycle regulator. The IRF3-RB interaction attenuates CDK4/6-mediated hyperphosphorylation of RB that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within CCl4 or bile duct ligation (BDL)-induced murine models, pushing activated HSCs towards senescence. Accordingly, global IRF3 knockout or conditional deletion of IRF3 in HSCs aggravated liver fibrosis, a process mitigated by an FDA-approved CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.

2024-12-31 | GSE252219 | GEO

Senescence progression in the normal human fibroblast, WI-38 cells induced with plasma membrane damage, calcium influx, DNA damage and telomere shortening.

Project description:To investigate the comparison of senescence progression in plasma membrane damage-, calcium influx-, DNA damage- and telomere shortening-induced senescence in the normal human fibroblast cells.

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Plasma Membrane Integrity Signaling

Project description:Plasma Membrane Integrity Signaling

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Expression data MCF10A/ErbB2 RB-proficient and RB-deficient cells cultured in 3-D cell culture

Project description:Gene expression analysis for structural components in Rb-deficient and RB-proficient ErbB2-overexpressing immortalized breast cell line using 3-D cell culture model to analyze structural and organizational changes of epithelial cells. Cells were cultured in a reconstituted membrane for 7 days. Cells were extracted with the use RNA-STAT-60 method.

2013-03-01 | E-GEOD-36425 | biostudies-arrayexpress

Amycolatopsis mediterranei RB strain:RB

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Plasma Membrane Integrity Signaling

Project description:To understand the transcriptional response of mammalian cells to plasma membrane stress we induced partial loss of plasmid membrane integrity by chemogenetic induction of pore forming proteins (Gasderimin and MLKL) or treatment with the detergent digitonin. We monitored transcription with mRNAseq in the immediate hours after plasma membrane damage and identified conserved transcriptional programs.

2021-10-04 | GSE166538 | GEO

Genome-wide analysis of RB and p130 binding in human diploid fibroblasts

Project description:The action of RB as a tumor suppressor has been difficult to define, in part, due to the redundancy of the related proteins p107 and p130. By coupling advanced RNAi technology with a genome wide analysis of gene expression and RB chromatin binding, we identified a unique and specific activity of RB in repressing DNA replication as cells exit the cell cycle into senescence, a tumor suppressive program. Binding of RB was examined in growing, quiescent, senescent or senescent cells lackign RB. Binding of p130 was examined in quiescent or senescent cells in the presence or absence of RB. Libraries were prapered from DNA co-precipiated with RB or p130 specific antibodies or from mock (beads-only) immunoprecipiates.

2010-01-15 | E-GEOD-19898 | biostudies-arrayexpress

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