Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype

Malaquin, Nicolas; Martinez, Aurélie; Rodier, Francis

doi:10.1016/j.exger.2016.05.010

Cited by 197 publications

(168 citation statements)

References 150 publications

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“…Although numerous stresses can cause cells to enter a senescent state, a SASP containing factors involved in tissue remodeling and repair has been detected only in cells that had undergone senescence due to activation of a persistent DNA damage response (DDR) (Malaquin, Martinez, & Rodier, 2016; Rodier et al, 2009). In these cells, the SASP develops dynamically and changes its composition in a temporal manner.…”

Section: Introductionmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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Cells that had undergone telomere dysfunction‐induced senescence secrete numerous cytokines and other molecules, collectively called the senescence‐associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF‐β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS‐dependent manner. Surprisingly, instead of activating cellular senescence, TGF‐β1‐induced telomere dysfunction caused fibroblasts to transdifferentiate into α‐SMA‐expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF‐β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF‐β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

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Section: Introductionmentioning

confidence: 99%

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

2018

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“…Естественно, что появляются работы по диаг-ностике SASP. Их цель -внедрение методов диагно-стики SASP в клиническую практику [35].…”

Section: Yb-1 и секреторный фенотип клеточных популяцийunclassified

“…Это свидетельствует о том, что клетки нейробластом in vivo и in vitro секретируют белок YB-1. Вполне вероятно, что этот феномен связан с КС, поскольку известно, что химиотерапия может индуцировать КС [35][36][37].…”

Section: Yb-1 и секреторный фенотип клеточных популяцийunclassified

Secreted protein YB-1 and its prognostic significance

Stavrovskaya¹,

Моисеева²,

Генс³

et al. 2017

Usp. mol. onkol

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Введение Данный обзор посвящен секретируемому белку YB-1 (secreted Y box-binding protein 1, сYB-1). Однако основные сведения относительно участия этого белка в процессах канцерогенеза и опухолевой прогрессии получены при изучении внутриклеточного белка YB-1, поэтому сначала остановимся на его значении для жиз-недеятельности клетки, связанном с его цитоплазмен-ной и ядерной локализацией. YB-1 -многофункцио-нальный белок, принадлежащий к суперсемейству белков, обладающих эволюционно консервативным доменом холодового шока (CSD), взаимодействующих с ДНК и РНК клетки [1,2].Интерес к YB-1 и его внутриклеточной локализации начался с работы R. C. Bargou и соавт. в 1997 г., в кото-рой было показано, что YB-1 является транскрипци-онным фактором для гена MDR1, кодирующего белок Р-гликопротеин, основного АВС-транспортера, ответ-ственного за множественную лекарственную устойчи-вость [3]. С этого момента количество работ, посвящен-ных YB-1 как в связи с множественной лекарственной устойчивостью [4,5], так и с другими аспектами опу-холевой прогрессии постоянно возрастало. Показано, что YB-1 участвует в регуляции многих клеточных про-цессов, включая пролиферацию, дифференцировку и ответ на стрессовые воздействия [6,7].

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“…A finer, potentially complementary approach may be to manipulate the SASP itself to eliminate long-term detrimental effects, such as chronic inflammation and impaired regeneration, while maintaining short-term beneficial effects (e.g. cancer prevention and wound healing; reviewed by Malaquin et al 2016). …”

Section: New Compounds Specifically Developed To Target Ageingmentioning

confidence: 99%

Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks

Mallikarjun

Swift

2016

EBioMedicine

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Ageing is a leading risk factor for many debilitating diseases. While age-related diseases have been the subject of over a century of intense investigation, until recently, physiological ageing was considered unavoidable. Pharmacological and genetic studies have since shown that ageing is a malleable process and that its abrogation can prevent its associated diseases. This review summarises a sample of the most promising efforts to deliver the products of ageing research to the clinic. Current efforts include the use of clinically approved drugs that have since been repurposed, as well as the development of novel therapeutics, to target ageing. Furthermore, ongoing research has sought reliable biomarkers of ageing that will accelerate the development of such therapeutics. Development of these technologies will improve quality of late-life and help relieve the enormous stress placed on state healthcare systems by a rapidly ageing global population. Thus, for both medical and socioeconomic reasons, it is imperative that ageing is made to yield to intervention.

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Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype

Cited by 197 publications

References 150 publications

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts

Secreted protein YB-1 and its prognostic significance

Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks

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