Publications
132 results found
Herranz N, Gallage S, Mellone M, et al., 2015, mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype, Nature Cell Biology, Vol: 17, Pages: 1205-1217, ISSN: 1476-4679
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
Ozmadenci D, Féraud O, Markossian S, et al., 2015, Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance, Nature Communications, Vol: 6, ISSN: 2041-1723
The generation of induced pluripotent stem (iPS) cells holds great promise in regenerative medicine. The use of the transcription factors Oct4, Sox2, Klf4 and c-Myc for reprogramming is extensively documented, but comparatively little is known about soluble molecules promoting reprogramming. Here we identify the secreted cue Netrin-1 and its receptor DCC, described for their respective survival/death functions in normal and oncogenic contexts, as reprogramming modulators. In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of Netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex. Mechanistically, Netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the Netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency. Our work also sheds light on Netrin-1's function in protecting embryonic stem cells from apoptosis mediated by its receptor UNC5b, and shows that the treatment with recombinant Netrin-1 improves the generation of mouse and human iPS cells.
O'Loghlen A, Martin N, Krusche B, et al., 2015, The nuclear receptor NR2E1/TLX controls senescence, Oncogene, Vol: 34, Pages: 4069-4077, ISSN: 0950-9232
The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21CIP1 or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16INK4a and direct repression of p21CIP1. In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.
Guerrero A, Iglesias C, Raguz S, et al., 2015, The cerebral cavernous malformation 3 gene is necessary for senescence induction, AGING CELL, Vol: 14, Pages: 274-283, ISSN: 1474-9718
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- Citations: 14
Martin N, Beach D, Gill J, 2014, Ageing as developmental decay: insights from p16<SUP>INK4a</SUP>, TRENDS IN MOLECULAR MEDICINE, Vol: 20, Pages: 667-674, ISSN: 1471-4914
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- Citations: 44
Santos J, Gil J, 2014, TRIM28/KAP1 regulates senescence, IMMUNOLOGY LETTERS, Vol: 162, Pages: 281-289, ISSN: 0165-2478
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- Citations: 14
Gil J, O'Loghlen A, 2014, PRC1 complex diversity: where is it taking us?, TRENDS IN CELL BIOLOGY, Vol: 24, Pages: 632-641, ISSN: 0962-8924
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- Citations: 117
Vizioli MG, Santos J, Pilotti S, et al., 2014, Oncogenic <i>RAS</i>-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved, ONCOTARGET, Vol: 5, Pages: 8270-8283
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- Citations: 19
Gallage S, Gil J, 2014, Primary cilia and senescence: A sensitive issue, CELL CYCLE, Vol: 13, Pages: 2653-2654, ISSN: 1538-4101
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- Citations: 2
Warboys CM, de Luca A, Amini N, et al., 2014, Disturbed flow promotes endothelial senescence via a p53-dependent Ppathway, Arteriosclerosis, Thrombosis and Vascular Biology, Vol: 34, Pages: 985-995, ISSN: 1079-5642
Objective—Although atherosclerosis is associated with systemic risk factors such as age, high cholesterol, and obesity, plaque formation occurs predominately at branches and bends that are exposed to disturbed patterns of blood flow. The molecular mechanisms that link disturbed flow–generated mechanical forces with arterial injury are uncertain. To illuminate them, we investigated the effects of flow on endothelial cell (EC) senescence.Approach and Results—LDLR−/− (low-density lipoprotein receptor−/−) mice were exposed to a high-fat diet for 2 to 12 weeks (or to a normal chow diet as a control) before the assessment of cellular senescence in aortic ECs. En face staining revealed that senescence-associated β-galactosidase activity and p53 expression were elevated in ECs at sites of disturbed flow in response to a high-fat diet. By contrast, ECs exposed to undisturbed flow did not express senescence-associated β-galactosidase or p53. Studies of aortae from healthy pigs (aged 6 months) also revealed enhanced senescence-associated β-galactosidase staining at sites of disturbed flow. These data suggest that senescent ECs accumulate at disturbed flow sites during atherogenesis. We used in vitro flow systems to examine whether a causal relationship exists between flow and EC senescence. Exposure of cultured ECs to flow (using either an orbital shaker or a syringe-pump flow bioreactor) revealed that disturbed flow promoted EC senescence compared with static conditions, whereas undisturbed flow reduced senescence. Gene silencing studies demonstrated that disturbed flow induced EC senescence via a p53-p21 signaling pathway. Disturbed flow–induced senescent ECs exhibited reduced migration compared with nonsenescent ECs in a scratch wound closure assay, and thus may be defective for arterial repair. However, pharmacological activation of sirtuin 1 (using resveratrol or SRT1720) protected ECs from disturbed flow&ndas
Wu H-A, Balsbaugh JL, Chandler H, et al., 2013, Mitogen-activated Protein Kinase Signaling Mediates Phosphorylation of Polycomb Ortholog Cbx7, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 36398-36408
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- Citations: 9
Millanes-Romero A, Herranz N, Perrera V, et al., 2013, Regulation of Heterochromatin Transcription by Snail1/LOXL2 during Epithelial-to-Mesenchymal Transition, MOLECULAR CELL, Vol: 52, Pages: 746-757, ISSN: 1097-2765
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- Citations: 81
Gomez-Cabello D, Adrados I, Gamarra D, et al., 2013, DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts, AGING CELL, Vol: 12, Pages: 923-931, ISSN: 1474-9718
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- Citations: 23
Acosta JC, Banito A, Wuestefeld T, et al., 2013, A complex secretory program orchestrated by the inflammasome controls paracrine senescence, Nature Cell Biology, Vol: 15, Pages: 978-U221, ISSN: 1465-7392
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 p15INK4b and p21CIP1. 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.
Martin N, Raguz S, Dharmalingam G, et al., 2013, Co-regulation of senescence-associated genes by oncogenic homeobox proteins and polycomb repressive complexes, CELL CYCLE, Vol: 12, Pages: 2194-2199, ISSN: 1538-4101
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- Citations: 10
Martin N, Popov N, Aguilo F, et al., 2013, Interplay between Homeobox proteins and Polycomb repressive complexes in p16<SUP>INK4a</SUP> regulation, EMBO JOURNAL, Vol: 32, Pages: 982-995, ISSN: 0261-4189
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- Citations: 32
Angeles Marques-Torrejon M, Porlan E, Banito A, et al., 2013, Cyclin-Dependent Kinase Inhibitor p21 Controls Adult Neural Stem Cell Expansion by Regulating Sox2 Gene Expression, CELL STEM CELL, Vol: 12, Pages: 88-100, ISSN: 1934-5909
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- Citations: 137
Banito A, Gil J, 2013, Enhancing reprogramming to pluripotency by controlling senescence, Tumor Dormancy, Quiescence, and Senescence: Aging, Cancer, and Noncancer Pathologies, Pages: 195-205, ISBN: 9789400759572
Induced pluripotent stem (iPS) cells can be obtained through the reprogramming of somatic cells by ectopic expression of defined factors. These cells hold immense promise for autologous cell therapy and disease modeling however, understanding the mechanistic of direct reprogramming is also shedding light into important biological processes. Several studies have shown how key tumor suppressors may interfere with reprogramming efficiency by activating cell-intrinsic programmes such as senescence and apoptosis. The repercussions of these findings are profound and reveal a link between tumor suppression and loss of differentiation. Here we analyze the latest findings in the field and discuss their relevance for iPS technology and tumor development.
Acosta JC, Snijders AP, Gil J, 2013, Unbiased characterization of the senescence-associated secretome using SILAC-based quantitative proteomics., Methods Mol Biol, Vol: 965, Pages: 175-184
Approaches based on the combination of mass spectrometry (MS) and quantitative methods have the potential to generate unbiased, thorough proteomic catalogues. In particular, stable isotope labeling with amino acid in cell culture (SILAC) has been used to perform highly accurate quantitative comparisons between the proteomes of different cell lines, treatments, or even animal models. Here, we describe how we have taken advantage of SILAC-based quantitative proteomics and inducible cell systems of oncogene-induced senescence to make an unbiased characterization of the senescence-associated secretome. This approach could be used to analyze the effect of diverse molecules on the senescence secretome or to catalogue unrelated secretomes.
Percharde M, Lavial F, Ng J-H, et al., 2012, Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming, GENES & DEVELOPMENT, Vol: 26, Pages: 2286-2298, ISSN: 0890-9369
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- Citations: 64
Acosta JC, Gil J, 2012, Senescence: a new weapon for cancer therapy, TRENDS IN CELL BIOLOGY, Vol: 22, Pages: 211-219, ISSN: 0962-8924
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- Citations: 163
O'Loghlen A, Munoz-Cabello AM, Gaspar-Maia A, et al., 2012, MicroRNA Regulation of Cbx7 Mediates a Switch of Polycomb Orthologs during ESC Differentiation, CELL STEM CELL, Vol: 10, Pages: 33-46, ISSN: 1934-5909
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- Citations: 164
Kang T-W, Yevsa T, Woller N, et al., 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, NATURE, Vol: 479, Pages: 547-551, ISSN: 0028-0836
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- Citations: 1007
Sun X-M, Patel DD, Acosta J-C, et al., 2011, Premature Senescence in Cells From Patients With Autosomal Recessive Hypercholesterolemia (ARH): Evidence for a Role for ARH in Mitosis, Arteriosclerosis, thrombosis, and vascular biology, Vol: 31, Pages: 2270-7
The ARH protein is involved in cell cycle progression, possibly by affecting nuclear membrane formation through interaction with lamin B1 or other mitotic proteins, and its absence affects cell proliferation and induces premature senescence, which may play a role in the development of atherosclerosis in ARH.
Smith L-L, Yeung J, Zeisig BB, et al., 2011, Functional Crosstalk between Bmi1 and MLL/Hoxa9 Axis in Establishment of Normal Hematopoietic and Leukemic Stem Cells, Cell stem cell, Vol: 8, Pages: 649-62
Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1(-/-) cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1(-/-) cells. MLL-AF9 could not initiate leukemia in Bmi1(-/-)Hoxa9(-/-) mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16(Ink4a)/p19(ARF) locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs.
Krupa M, Canamero M, Gomez CE, et al., 2011, Immunization with recombinant DNA and modified vaccinia virus Ankara (MVA) vectors delivering PSCA and STEAP1 antigens inhibits prostate cancer progression, Vaccine, Vol: 29, Pages: 1504-13
Despite recent advances in early detection and improvement of conventional therapies, there is an urgent need for development of additional approaches for prevention and/or treatment of prostate cancer, and the use of immunotherapeutic modalities, such as cancer vaccines, is one of the most promising strategies. In this study, we evaluated the prophylactic efficacy of an active immunization protocol against prostate cancer associated antigens mPSCA and mSTEAP1 in experimental prostate cancer. Two antigen delivery platforms, recombinant DNA and MVA vectors, both encoding either mPSCA or mSTEAP1 were used in diversified DNA prime/MVA boost vaccination protocol. Antitumour activity was evaluated in TRAMP-C1 subcutaneous syngeneic tumour model and TRAMP mice. DNA prime/MVA boost immunization against either mPSCA or mSTEAP1, delayed tumour growth in TRAMP-C1 cells-challenged mice. Furthermore, simultaneous vaccination with both antigens produced a stronger anti-tumour effect against TRAMP-C1 tumours than vaccination with either mPSCA or mSTEAP1 alone. Most importantly, concurrent DNA prime/MVA boost vaccination regimen with those antigens significantly decreased primary tumour burden in TRAMP mice without producing any apparent adverse effects. Histopathological analysis of prostate tumours from vaccinated and control TRAMP mice revealed also that mPSCA/mSTEAP1 based-vaccination was effective at reducing the severity of prostatic lesions and incidence of high-grade poorly differentiated prostate cancer. Suppression of the disease progression in TRAMP mice was correlated with decreased proliferation index and increased infiltration of T-cells in prostate tissue. Active immunization against PSCA and STEAP1 using DNA prime/MVA boost strategy is a promising approach for prevention and/or treatment of prostate cancer.
Popov N, Gil J, 2010, Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health, Epigenetics, Vol: 5, Pages: 685-90
The INK4b-ARF-INK4a locus encodes for two cyclin-dependent kinase inhibitors, p15(INK4b) and p16(INK4a) and a regulator of the p53 pathway, ARF. In addition ANRIL, a non-coding RNA, is also transcribed from the locus. ARF, p15(INK4b) and p16(INK4a) are well-established tumor suppressors which function is frequently disabled in human cancers. Recent studies showed that single nucleotide polymorphisms mapping in the vicinity of ANRIL are linked to a wide spectrum of conditions, including cardiovascular disease, ischemic stroke, type 2 diabetes, frailty and Alzheimer’s disease. The INK4b-ARF-INK4a locus is regulated by Polycomb repressive complexes (PRCs), and its expression can be invoked by activating signals. Other epigenetic modifiers such as the histone demethylases JMJD3 and JHDM1B, the SWI/SNF chromatin remodeling complex and DNA methyltransferases regulate the locus interplaying with PRCs. In view of the intimate involvement of the INK4b-ARF-INK4a locus on disease, to understand its regulation is the first step for manipulate it to therapeutic benefit.
Yap KL, Li S, noz-Cabello AMM, et al., 2010, Molecular Interplay of the Noncoding RNA ANRIL and Methylated Histone H3 Lysine 27 by Polycomb CBX7 in Transcriptional Silencing of INK4a, Mol Cell, Vol: 38, Pages: 662-674
Molecular Cell, 38 (2010) 662-674. doi:10.1016/j.molcel.2010.03.021
Banito A, Gil J, 2010, Induced pluripotent stem cells and senescence: learning the biology to improve the technology, EMBO reports
The discovery that adult somatic cells can be reprogrammed into pluripotent cells by expressing a combination of factors associated with pluripotency holds immense promise for a wide range of biotechnological and therapeutic applications. However, some hurdles-such as improving the low reprogramming efficiencies and ensuring the pluripotent potential, genomic integrity and safety of the resulting cells-must be overcome before induced pluripotent stem cells (iPSCs) can be used for clinical purposes. Several groups have recently shown that key tumour suppressors-such as members of the p53 and p16(INK4a)/retinoblastoma networks-control the efficiency of iPSC generation by activating cell-intrinsic programmes such as senescence. Here, we discuss the implications of these discoveries for improving the safety and efficiency of iPSC generation, and for increasing our understanding of different aspects of basic biology-such as the control of pluripotency or the mechanisms involved in the generation of cancer stem cells.
Pereira CF, Piccolo FM, Tsubouchi T, et al., 2010, ESCs Require PRC2 to Direct the Successful Reprogramming of Differentiated Cells toward Pluripotency, Cell stem cell, Vol: 6, Pages: 547-556
Stem Cell, 6 (2010) 547-556. doi:10.1016/j.stem.2010.04.013
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