Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence

Acosta, Juan Carlos; O’Loghlen, Ana; Banito, Ana; Guijarro, María V.; Augert, Arnaud; Raguz, Selina; Fumagalli, Marzia; Costa, Marco Da; Brown, Celia; Popov, Nikolay; Takatsu, Yoshihiro; Melamed, Jonathan; Fagagna, Fabrizio d’Adda di; Bernard, David; Hernando, Eva; Gil, Jesús

doi:10.1016/j.cell.2008.03.038

Cited by 1,530 publications

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“…Cells were maintained in Dulbecco's modified Eagle's medium (Invitrogen, Paisley, UK) with 10% foetal bovine serum (PAA, Amersham, UK) and 1% antibiotic–antimycotic solution (Invitrogen, Paisley, UK). Methods used for retrovirus production and infection have been described previously (Acosta et al ., 2008). …”

Section: Methodsmentioning

confidence: 99%

“…BrdU labelling was performed for 24 h. Crystal violet staining was performed as previously described (Acosta et al ., 2008). …”

Section: Methodsmentioning

confidence: 99%

“…SA‐β‐Galactosidase staining and quantification was performed as previously described (Acosta et al ., 2008). For SAHF quantification, cells were stained with DAPI and the nuclei of at least 100 cells per condition were assessed.…”

Section: Methodsmentioning

confidence: 99%

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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SummaryPolycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR‐9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR‐9‐1 and miR‐9‐2 as part of a regulatory negative feedback loop. The miR‐9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin‐dependent kinase inhibitor (CDKI) p16INK 4a during senescence. The ability of the miR‐9 family to regulate senescence could have implications for understanding the role of miR‐9 in cancer and aging.

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Section: Methodsmentioning

confidence: 99%

“…BrdU labelling was performed for 24 h. Crystal violet staining was performed as previously described (Acosta et al ., 2008). …”

Section: Methodsmentioning

confidence: 99%

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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“…We particularly focused on NF‐κB transcription factors, as they were reported to induce SCN9A expression in neurons (Huang et al., 2014) and are well‐known regulators of senescence (Acosta et al., 2008; Bernard et al., 2004; Chien et al., 2011; Ferrand et al., 2015). We examined whether or not the inhibition of NF‐κB transcription factors, either by constitutively expressing a stabilized version of IKBA (mIKBA), a well‐known inhibitor of NF‐κB, or by knocking down the expression of RELA (Figures 2a and S3a), the main subunit of the NF‐κB transcription factors, blocked the induction of SCN9A during OIS.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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SummaryOncogenic 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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“…In agreement with the X‐Gal data, Galacton revealed a massive induction of senescence in the kidneys of GCV‐treated mice (Figure 2f). We also measured the mRNA expression of different genes linked to the senescent cell response, such as Ink4a (Krishnamurthy et al, 2004), Ink4b (Malumbres et al, 2000), Il6 (Acosta et al, 2008; Kuilman et al, 2008), Mmp1 (Benanti, Williams, Robinson, Ozer, & Galloway, 2002), Serpine1 (Goldstein et al, 1994; Mu & Higgins, 1995), and Timp1 (Komosinska‐Vassev et al, 2011). In all cases, we observed a statistically significant increase in the levels of mRNA for these genes, in agreement with the notion of a strong induction of senescence, a response typically associated with advanced aging (Figure 2g).…”

Section: Introduction Results Discussionmentioning

confidence: 99%

Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging

et al. 2018

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Aging is characterized by a gradual functional decline of tissues with age. Adult stem and progenitor cells are responsible for tissue maintenance, repair, and regeneration, but during aging, this population of cells is decreased or its activity is reduced, compromising tissue integrity and causing pathologies that increase vulnerability, and ultimately lead to death. The causes of stem cell exhaustion during aging are not clear, and whether a reduction in stem cell function is a cause or a consequence of aging remains unresolved. Here, we took advantage of a mouse model of induced adult Sox2+ stem cell depletion to address whether accelerated stem cell depletion can promote premature aging. After a short period of partial repetitive depletion of this adult stem cell population in mice, we observed increased kyphosis and hair graying, and reduced fat mass, all of them signs of premature aging. It is interesting that cellular senescence was identified in kidney after this partial repetitive Sox2+ cell depletion. To confirm these observations, we performed a prolonged protocol of partial repetitive depletion of Sox2+ cells, forcing regeneration from the remaining Sox2+ cells, thereby causing their exhaustion. Senescence specific staining and the analysis of the expression of genetic markers clearly corroborated that adult stem cell exhaustion can lead to cellular senescence induction and premature aging.

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Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence

Cited by 1,530 publications

References 42 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

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

Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging

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Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence

Cited by 1,530 publications

References 42 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

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

Adult Sox2+ stem cell exhaustion in mice results in cellular senescence and premature aging

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Product

Resources

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a