Controversial aspects of oncogene-induced senescence

Bianchi‐Smiraglia, Anna; Nikiforov, Mikhail A.

doi:10.4161/cc.22589

Cited by 33 publications

(35 citation statements)

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“…Emerging evidences support the existence of other mechanisms regulating senescence escape. To date, little is known about these mechanisms (12)(13)(14)(15)(16)(17)(18). Similar data generated in human epithelial cells or in other lineages are rather rare and seem to display a more complex picture of the genetic events involved in senescence escape (18).…”

Section: Introductionmentioning

confidence: 74%

“…To date, little is known about these mechanisms (12)(13)(14)(15)(16)(17)(18). Similar data generated in human epithelial cells or in other lineages are rather rare and seem to display a more complex picture of the genetic events involved in senescence escape (18). As an example, poststasis human mammary epithelial cells (HMEC), which are not expressing the p16INK4A (19), enter in senescence in response to an oncogenic stress in a DNA damagep53-independent pathway (17,18).…”

Section: Introductionmentioning

confidence: 87%

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Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

et al. 2013

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Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway. Cancer Res; 73(16); 5253-65. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 87%

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

et al. 2013

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“…Nevertheless, a growing body of evidence supports the involvement of other pathways in the regulation of senescence, and in particular, in that of oncogene‐induced senescence (OIS) (Bianchi‐Smiraglia & Nikiforov, 2012; Christoffersen et al., 2010; Cipriano et al., 2011; Humbert et al., 2010; Lin et al., 2010; Scurr et al., 2010). …”

Section: Introductionmentioning

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 addition to proliferative arrest, OIS involves the activation of a variety of signaling pathways, and senescent cells are characterized by increased size, activation of β-galactosidase, chromatin aggregates enriched for H3K9me3, activated DNA damage markers, and extracellular matrixdegrading enzymes (reviewed in ref. 23).…”

Section: Cervical Cancer Cells Are Sensitive To Treatment With the Kdmentioning

confidence: 99%

Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

McLaughlin-Drubin

Park²,

Münger

2013

Proc. Natl. Acad. Sci. U.S.A.

148

146

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The tumor suppressor p16 INK4A inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins. Oncogenic stress induces p16 INK4A expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor. Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16 INK4A activity by mutation or epigenetic silencing. Human papillomavirus (HPV)-associated tumors express high levels of p16 INK4A in response to E7 oncoprotein expression. Induction of p16 INK4A expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B. HPV E7 expression causes an acute dependence on KDM6B expression for cell survival. The p16 INK4A tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival. This oncogenic p16 INK4A activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive. Finally, we note that HPV E7 expression creates a unique cellular vulnerability to small-molecule KDM6A/B inhibitors.synthetic lethality | apoptosis | biomarker | cancer therapy P osttranslational histone modifications, including phosphorylation, ubiquitination, acetylation, and methylation, impact both the physical state and the transcriptional competence of chromatin. These modifications are dynamic and regulate a variety of cellular processes, such as stem cell maintenance, cell fate determination and maintenance, cell cycle control, and epigenetic heritability of transcriptional programs (reviewed in refs. 1 and 2). Methylation of lysine residues on histones is modulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). Although histone lysine methylation is involved in both transcriptional activation and repression, histone H3 trimethylation of lysine 27 (H3K27me3) on gene promoters is crucial for epigenetic silencing mediated by polycomb group proteins (3-5). The JmjC-domain containing histone demethylases, KDM6A (UTX) and KDM6B (JMJD3) remove this repressive mark, allowing for transcriptional activation (6-10). Although KDM6A and KDM6B appear identical with regards to catalytic activities and histone substrate specificities, they have a number of nonoverlapping and nonredundant biological activities. KDM6B-but not KDM6A-regulates RAS/RAF-mediated oncogene-induced senescence (OIS) (11, 12). OIS was originally described as a cell-abortive response to ectopic RAS oncogene expression in normal human cells. It is now recognized that OIS represents one of several cell-intrinsic tumor-suppressor responses that function to eliminate aberrantly proliferating, potentially premalignant cells. Evidence for OIS has been dete...

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Controversial aspects of oncogene-induced senescence

Cited by 33 publications

References 105 publications

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

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

Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

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Controversial aspects of oncogene-induced senescence

Cited by 33 publications

References 105 publications

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

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

Tumor suppressor p16 INK4A is necessary for survival of cervical carcinoma cell lines

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Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines