A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Juan Carlos Acosta,Ana Banito,Torsten Wuestefeld,Athena Georgilis,Peggy Janich,Jennifer P. Morton,Dimitris Athineos,Tae-Won Kang,Felix Lasitschka,Mindaugas Andrulis,Gloria Pascual,Kelly J. Morris,Sadaf Khan,Hong Jin,Gopuraja Dharmalingam,Ambrosius P. Snijders,Thomas L. Carroll,David Capper,Catrin Pritchard,Gareth J. Inman,Thomas Longerich,Owen J. Sansom,Salvador Aznar Benitah,Lars Zender,Jesús Gil +24 more
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TLDR
It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.Abstract:
Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.read more
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Reducing Senescent Cell Burden in Aging and Disease.
TL;DR: It is hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine and target engagement of senolytic agents that clear senescent cells.
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The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
Priya Hari,Fraser R. Millar,Núria Tarrats,Jodie Birch,Andrea Quintanilla,Curtis J. Rink,Irene Fernández-Duran,Morwenna Muir,Andrew J. Finch,Valerie G. Brunton,João F. Passos,João F. Passos,Jennifer P. Morton,Luke Boulter,Juan Carlos Acosta +14 more
TL;DR: It is reported that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.
Journal ArticleDOI
Mesenchymal Stem Cells Secretory Responses: Senescence Messaging Secretome and Immunomodulation Perspective.
TL;DR: This review elucidates how autocrine and paracrine properties of senescent MSC might impose an additional layer of complexity on the regulation of the immune system in development and disease.
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IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2.
Sona Hubackova,A Kucerova,Georg Michlits,Lenka Kyjacova,Milan Reinis,O Korolov,Jiri Bartek,Zdenek Hodny +7 more
TL;DR: Differences between cytokine effects in mouse and human cells are revealed, and mechanistically implicate the TGFβ/SMAD pathway, via induction of NADPH oxidases and suppression of ANT2, as key mediators of IFNγ/TNFα-evoked genotoxicity and cellular senescence.
Journal ArticleDOI
Radiation induces senescence and a bystander effect through metabolic alterations
E. C. Liao,Y. T. Hsu,Q. Y. Chuah,Yi Jang Lee,J. Y. Hu,Tsui-Chin Huang,Pei Ming Yang,S. J. Chiu +7 more
TL;DR: It is found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis and increased the expression of monocarboxylate transporter 1 that facilitates the export of lactate into the extracellular environment.
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