86 results found
Young HL, Rowling EJ, Bugatti M, et al., 2017, An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition., J Exp Med, Vol: 214, Pages: 1691-1710, ISSN: 0022-1007
Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal-regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.
Adrados I, Larrasa-Alonso J, Galarreta A, et al., 2016, The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes, ONCOGENE, Vol: 35, Pages: 3485-3494, ISSN: 0950-9232
Cellular senescence is an antiproliferative response with essential functions in tumor suppression and tissue homeostasis. Here we show that SIX1, a member of the SIX family of homeobox transcriptional factors, is a novel repressor of senescence. Our data show that SIX1 is specifically downregulated in fibroblasts upon oncogenic stress and other pro-senescence stimuli, as well as in senescent skin premalignant lesions. Silencing of SIX1 in human fibroblasts suffices to trigger senescence, which is mediated by p16INK4A and lacks a canonical senescence-associated secretory phenotype. Interestingly, SIX1-associated senescence is further characterized by the expression of a set of development and differentiation-related genes that significantly overlap with genes associated with SIX1 in organogenesis or human tumors, and show coincident regulation in oncogene-induced senescence. Mechanistically, we show that gene regulation by SIX1 during senescence is mediated, at least in part, by cooperation with Polycomb repressive complexes. In summary, our results identify SIX1, a key development regulator altered in human tumors, as a critical repressor of cellular senescence, providing a novel connection between senescence, differentiation and tumorigenesis.
Apps JR, Jani N, Gonzalez-Meljem JM, et al., 2016, Clusters of Nuclear Beta-Catenin Accumulating Cells Form Secretory Hubs in Adamantinomatous Craniopharyngioma, 205th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY-BLACKWELL, Pages: S5-S5, ISSN: 0022-3417
Cellular senescence and mitochondrial dysfunction are hallmarks of ageing, but until now their relationship has not been clear. Recent work by Wiley et al. shows that mitochondrial defects can cause a distinct senescence phenotype termed MiDAS (mitochondrial dysfunction-associated senescence). MiDAS has a specific secretome that is able to drive some of the aging phenotypes. These findings suggest novel therapeutic opportunities for treating age-related pathologies.
The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue of Genes & Development, Bent and colleagues (pp. 1811-1821) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation.
Gil J, Rodriguez T, Gil J, et al., 2016, Cancer: The Transforming Power of Cell Competition, CURRENT BIOLOGY, Vol: 26, Pages: R164-R166, ISSN: 0960-9822
The tumour-host microenvironment plays key roles in cancer, but the mechanisms involved are not fully understood. Two new studies provide insight into this problem by showing that through cell competition, a fitness-sensing process that usually eliminates defective cells, pre-cancerous lesions signal the death of surrounding tissue that in turn promotes their neoplastic transformation.
The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes.
Guerrero A, Gil J, Guerrero A, et al., 2016, HMGB2 holds the key to the senescence-associated secretory phenotype., J Cell Biol, Vol: 215, Pages: 297-299, ISSN: 0021-9525
The senescence-associated secretory phenotype (SASP) is a hallmark of senescence with an important physiological impact, but how it is established is unclear. In this issue, Aird et al. (2016. J. Cell Biol. https://doi.org/10.1083/jcb.201608026) describe how chromatin-bound HMGB2 fine tunes SASP expression by avoiding heterochromatin spreading.
Herranz N, Gil J, Herranz N, et al., 2016, Mitochondria and senescence: new actors for an old play, EMBO JOURNAL, Vol: 35, Pages: 701-702, ISSN: 0261-4189
Mitochondrial dysfunction has been linked to both cellular senescence and ageing. Despite the relationship, it is still unclear whether mitochondria have a causal role in senescence. In this issue of The EMBO Journal, Correia-Melo et al (2016) combine targeted depletion of mitochondria with impairment of their biogenesis to demonstrate that decreased numbers of mitochondria impair the senescence response. Their results suggest that targeting mitochondria could reduce the detrimental effects of senescence during ageing.
Mellone M, Hanley CJ, Thirdborough S, et al., 2016, Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis., Aging (Albany NY), Vol: 9, Pages: 114-132, ISSN: 1945-4589
Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-β signaling. Similar to TGF-β1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.
Tordella L, Khan S, Hohmeyer A, et al., 2016, SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer, GENES & DEVELOPMENT, Vol: 30, Pages: 2187-2198, ISSN: 0890-9369
Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16(INK4a) and p21(CIP1a) transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/SNF-mutated cancers.
Wong CL, Innes A, Ma B, et al., 2016, Differential Expression of Genes Associated with Oncogene-Induced Senescence and Senescence Associated Secretory Phenotype in the Absence of Differential Expression of High Molecular Risk Genes and Genes Associated with JAK-STAT Pathway in Sorted Cells of Patients with Polycythemia Vera and Primary Myelofibrosis, 58th Annual Meeting and Exposition of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, Pages: 4283-4283, ISSN: 0006-4971
Esposito MT, Zhao L, Fung TK, et al., 2015, 7Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors, NATURE MEDICINE, Vol: 21, Pages: 1481-+, ISSN: 1078-8956
Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors, which have been classically viewed as intractable targets using small-molecule inhibitor approaches. Here we demonstrate that AML driven by repressive transcription factors, including AML1-ETO (encoded by the fusion oncogene RUNX1-RUNX1T1) and PML-RARα fusion oncoproteins (encoded by PML-RARA) are extremely sensitive to poly (ADP-ribose) polymerase (PARP) inhibition, in part owing to their suppressed expression of key homologous recombination (HR)-associated genes and their compromised DNA-damage response (DDR). In contrast, leukemia driven by mixed-lineage leukemia (MLL, encoded by KMT2A) fusions with dominant transactivation ability is proficient in DDR and insensitive to PARP inhibition. Intriguingly, genetic or pharmacological inhibition of an MLL downstream target, HOXA9, which activates expression of various HR-associated genes, impairs DDR and sensitizes MLL leukemia to PARP inhibitors (PARPis). Conversely, HOXA9 overexpression confers PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these studies describe a potential utility of PARPi-induced synthetic lethality for leukemia treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML.
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
Mutations in cerebral cavernous malformation 3 gene are known to result in development of vascular malformations and have recently been proposed to also give rise to meningiomas. We report in this study that lack of CCM3 unexpectedly impairs the senescence response of cells, and this is related to the inability of CCM3-deficient cells to induce the C/EBPβ transcription factor and implement the senescence-associated secretory phenotype. Induction of C/EBPβ and cytokines is also impaired in the absence of CCM3 in response to cytokines in nonsenescent cells, pointing to it being a primary defect and not secondary to impaired senescence. CCM3-deficient cells also have a defect in autophagy at late passages of culture, and this defect is also not dependent on impaired senescence, as it is evident in immortal cells after nutrient starvation. Further, these two defects may be related, as enforcing autophagy in CCM3-deficient late passage cells increases C/EBPβ cytokine expression. These results broaden our knowledge on the mechanisms by which CCM3 deficiency results in disease and open new avenues of research into both CCM3 and senescence biology.
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-+, ISSN: 1465-7392
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.
Herranz N, Gallage S, Mellone M, et al., 2015, Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype., Nat Cell Biol, Vol: 17, Pages: 1370-1370, ISSN: 1465-7392
Lin M-L, Patel H, Remenyi J, et al., 2015, Expression profiling of nuclear receptors in breast cancer identifies TLX as a mediator of growth and invasion in triple-negative breast cancer, ONCOTARGET, Vol: 6, Pages: 21685-21703, ISSN: 1949-2553
The Nuclear Receptor (NR) superfamily of transcription factors comprises 48 members, several of which have been implicated in breast cancer. Most important is estrogen receptor-α (ERα), which is a key therapeutic target. ERα action is facilitated by co-operativity with other NR and there is evidence that ERα function may be recapitulated by other NRs in ERα-negative breast cancer. In order to examine the inter-relationships between nuclear receptors, and to obtain evidence for previously unsuspected roles for any NRs, we undertook quantitative RT-PCR and bioinformatics analysis to examine their expression in breast cancer. While most NRs were expressed, bioinformatic analyses differentiated tumours into distinct prognostic groups that were validated by analyzing public microarray data sets. Although ERα and progesterone receptor were dominant in distinguishing prognostic groups, other NR strengthened these groups. Clustering analysis identified several family members with potential importance in breast cancer. Specifically, RORγ is identified as being co-expressed with ERα, whilst several NRs are preferentially expressed in ERα-negative disease, with TLX expression being prognostic in this subtype. Functional studies demonstrated the importance of TLX in regulating growth and invasion in ERα-negative breast cancer cells.
O'Loghlen A, Brookes S, Martin N, et al., 2015, CBX7 and miR-9 are part of an autoregulatory loop controlling p16(INK4a), AGING CELL, Vol: 14, Pages: 1113-1121, ISSN: 1474-9718
Polycomb 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) p16(INK4a) 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.
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 p21(CIP1) 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 p16(INK4a) and direct repression of p21(CIP1). 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.
Ozmadenci D, Feraud O, Markossian S, et al., 2015, Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance, NATURE COMMUNICATIONS, Vol: 6, Pages: 7398-7398, 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.
Polycomb group proteins (PcGs) are essential epigenetic regulators that play key roles in development, pluripotency, senescence, and cancer. Recent reports have found that the composition of mammalian Polycomb repressive complex 1 (PRC1) is far more varied than previously thought. PRC1 diversity largely depends on the presence of CBX proteins, dividing them into canonical and non-canonical, the existence of redundant subunits, and different binding affinities and/or regulation. However, there is no clear insight into how many functional PRC1 complexes exist and what the biological relevance is for such diversification. In this review we focus on mammalian PRC1 and discuss the mechanisms by which canonical and non-canonical PRC1 are recruited to chromatin, their role in normal development and disease, and emerging evidence for PRC1 as a transcriptional activator.
Martin N, Beach D, Gill J, et al., 2014, Ageing as developmental decay: insights from p16(INK4a), TRENDS IN MOLECULAR MEDICINE, Vol: 20, Pages: 667-674, ISSN: 1471-4914
The p16(INK4a) cell cycle regulator is one of the best ageing biomarkers because it is suppressed in early embryogenesis and progressively induced during ageing. p16(INK4a) plays a crucial role in key cell fate decisions which contribute to ageing, such as cellular senescence and stem cell dynamics. Detailed examination of the pathways regulating p16(INK4a) expression has revealed an overlap with those regulating early development. We present the hypothesis that ageing might be primarily driven by gradual functional decay of developmental pathways. To support this, we summarise the role of p16(INK4a) in ageing and our current knowledge on p16(INK4a) regulation. The developmental decay hypothesis implies that the much-evidenced damage associated with all aspects of ageing might be secondary to such decay.
Senescence is a highly stable cell cycle arrest which limits the replication of cells with damaged genomes. The senescence program is activated during aging or in response to insults like DNA damage or oncogenic signaling. Upon induction of senescence, cells undergo profound changes on their transcription program, chromatin organization, and they secrete a complex mixture of mainly pro-inflammatory components termed the senescence-associated secretory phenotype (SASP). The SASP mediates multiple effects, including reinforcing senescence and activating immune surveillance responses. Given the important role that senescence has in aging, cancer and other pathologies, identifying mechanisms regulating senescence has therapeutic potential. Here we describe a role for TRIM28 (also known as KRAB-associated protein 1, KAP1) on mediating oncogene-induced senescence (OIS). TRIM28 accumulates during OIS becoming phosphorylated on serine 824. To investigate the role of TRIM28, we knocked down its expression and observed that the depletion of TRIM28 partially prevented cell arrest during OIS. While induction of p53 and p21 during OIS, was not affected by TRIM28 depletion, p16(INK4a) induction was partially prevented. Finally, we observed that the induction of IL8, IL6 and other SASP components were strongly suppressed upon TRIM28 depletion. In conclusion, the above-described results show that TRIM28 regulates senescence and affects the induction of the senescence-associated secretory phenotype.
Vizioli MG, Santos J, Pilotti S, et al., 2014, Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved, ONCOTARGET, Vol: 5, Pages: 8270-8283, ISSN: 1949-2553
Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response to oncogenic stress and constitutes an efficient barrier to tumour progression. We have recently proposed that OIS may be involved in the pathogenesis of thyroid carcinoma by restraining tumour progression as well as the transition of well differentiated to more aggressive variants. Here, an OIS inducible model was established and used for dissecting the molecular mechanisms and players regulating senescence in human primary thyrocytes. We show that oncogenic RAS induces senescence in thyrocytes as judged by changes in cell morphology, activation of p16INK4a and p53/p21CIP1 tumour suppressor pathways, senescence-associated β-galactosidase (SA-β-Gal) activity, and induction of proinflammatory components including IL-8 and its receptor CXCR2. Using RNA interference (RNAi) we demonstrate that p16INK4a is necessary for the onset of senescence in primary thyrocytes as its depletion rescues RAS-induced senescence. Furthermore, we found that IL-8/CXCR2 network reinforces the growth arrest triggered by oncogenic RAS, as its abrogation is enough to resume proliferation. Importantly, we observed that CXCR2 expression coexists with OIS markers in thyroid tumour samples, suggesting that CXCR2 contributes to senescence, thus limiting thyroid tumour progression.
Warboys CM, de Luca A, Amini N, et al., 2014, Disturbed Flow Promotes Endothelial Senescence via a p53-Dependent Pathway, 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-induced senescence. CONCLUSIONS: Disturbed fl
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 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.
Acosta JC, Snijders AP, Gil J, et al., 2013, Unbiased characterization of the senescence-associated secretome using SILAC-based quantitative proteomics., Methods Mol Biol, Vol: 965, Pages: 175-184, ISSN: 1064-3745
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.
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
In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21 null cells induce replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19(Arf) and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.
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