The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway
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PROVIDER: PRJNA434736 | ENA |
REPOSITORIES: ENA
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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
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-κB 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-κB 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.
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Project description:After depolarization treatment, a series of membrane protein were changed significantly. We collected the total membrane protein of the mouse peritoneal macrophages as previously (Karmakar et al., 2020), and then analyzed by Mass Spectrometry
2022-05-07 | PXD033322 | Pride
Project description:Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts, blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating factors. Due to these adverse effects, preosteoblast senescence is a crucial target for the treatment of age-related bone loss; however, the underlying mechanism remains unclear. We found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse model. Mechanistically, mTORC1 induced a change in the membrane potential from polarization to depolarization, thus promoting cell senescence by increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. We further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent preosteoblasts. Scn1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα, whereas its permeability to Na+ was found to be gated by protein kinase A (PKA)-induced phosphorylation. Prosenescent stresses increased the permeability of Scn1a to Na+ by suppressing PKA activity and induced depolarization in preosteoblasts. Together, our findings identify a novel pathway involving mTORC1, Scn1a expression and gating, plasma membrane depolarization, increased Ca2+ influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast senescence. Pharmaceutical studies of the related pathways and agents might lead to novel potential treatments for age-related bone loss.
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Project description:Upon mitochondrial dysfunction, mitophagy has been described to be activated by a breakdown of membrane potential leading to PINK1 accumulation on the outer membrane and engulfment of mitochondria for degradation. However, recent findings have indicated that mitophagy may also be triggered in the absence of membrane potential alterations. Here, we report mechanistic details on how inhibition of protein import induces mitophagy independent of mitochondrial membrane depolarization. Carrying out a genome-wide CRISPR/Cas9 screen for regulators of mitophagy, we found that the pre-sequence translocase-associated motor complex PAM controls mitophagy induction. Loss of PAM caused defects in protein import and was sufficient to induce mitophagy without depolarization. Quantitative interaction and aggregation proteomics revealed that PAM was highly sensitive to proteostasis perturbation; upon misfolding conditions, PAM dissociated from the import machinery, sequestered into the insoluble fraction and caused mitophagy despite an intact membrane potential. Our findings extend the current mitophagy model and provide mechanistic insight into how proteostasis perturbation leads to mitophagy induction. They reveal the PAM complex as key folding sensor integrating proteostasis, import and mitophagy.
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Project description:Salamanders, such as the Mexican axolotl, are some of the few vertebrates fortunate in their ability to regenerate diverse structures after injury. Unlike mammals they are able to regenerate a fully functional spinal cord after injury. However, the early signals required to initiate a pro-regenerative response after spinal cord injury is not well understood. To address this question we developed a spinal cord injury model in axolotls and used in vivo imaging of ion sensitive dyes and determined that spinal cord injury induces a rapid and dynamic change in the resting membrane potential of ependymoglial cells. Prolonged depolarization of ependymoglial cells after injury inhibits glial cell proliferation and subsequent axon regeneration. Using transcriptional profiling we identified c-Fos as a key voltage sensitive early response gene that is expressed specifically in the ependymoglial cells after injury. This data establishes that dynamic changes in the membrane potential after injury are essential for regulating the specific spatiotemporal expression of c-Fos that is critical for promoting faithful spinal cord regeneration in axolotl.
2016-01-03 | GSE71934 | GEO
Project description:Plasma Membrane Integrity Signaling
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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.
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