Non-Cell-Autonomous Tumor Suppression by p53

Lujambio, Amaia; Akkari, Leila; Simon, Janelle; Grace, Danielle; Tschaharganeh, Darjus F.; Bolden, Jessica E.; Zhao, Zhen; Thapar, Vishal; Joyce, Johanna A.; Krizhanovsky, Valery; Lowe, Scott W.

doi:10.1016/j.cell.2013.03.020

Cited by 632 publications

(596 citation statements)

References 48 publications

(77 reference statements)

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“…other components of the innate immune system, including natural killer (NK) cells, neutrophils, dendritic cells, and macrophages, functionally contribute to elimination of senescent cells (11,15,21). NK cells, for example, have been shown to recognize and eliminate senescent cells after expression of NK receptor ligands, adhesion molecules (intercellular adhesion molecule-1), and death receptors (TRAIL-R and FAS), respectively (10,11,15).…”

Section: Significancementioning

confidence: 99%

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Frescas

Roux

Aygun‐Sunar

et al. 2017

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

113

103

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Studying the phenomenon of cellular senescence has been hindered by the lack of senescence-specific markers. As such, detection of proteins informally associated with senescence accompanies the use of senescence-associated β-galactosidase as a collection of semiselective markers to monitor the presence of senescent cells. To identify novel biomarkers of senescence, we immunized BALB/c mice with senescent mouse lung fibroblasts and screened for antibodies that recognized senescence-associated cell-surface antigens by FACS analysis and a newly developed cell-based ELISA. The majority of antibodies that we isolated, cloned, and sequenced belonged to the IgM isotype of the innate immune system. In-depth characterization of one of these monoclonal, polyreactive natural antibodies, the IgM clone 9H4, revealed its ability to recognize the intermediate filament vimentin. By using 9H4, we observed that senescent primary human fibroblasts express vimentin on their cell surface, and MS analysis revealed a posttranslational modification on cysteine 328 (C328) by the oxidative adduct malondialdehyde (MDA). Moreover, elevated levels of secreted MDA-modified vimentin were detected in the plasma of aged senescence-accelerated mouse prone 8 mice, which are known to have deregulated reactive oxygen species metabolism and accelerated aging. Based on these findings, we hypothesize that humoral innate immunity may recognize senescent cells by the presence of membrane-bound MDA-vimentin, presumably as part of a senescence eradication mechanism that may become impaired with age and result in senescent cell accumulation.aging | oxidative posttranslational modifications | biomarker | SAMP8 | malondialdehyde

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Section: Significancementioning

confidence: 99%

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Frescas

Roux

Aygun‐Sunar

et al. 2017

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

113

103

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“…Macrophages also display an immunosurveillance role against senescent cells within tissues under physiological and pathological conditions. For example, during liver fibrosis, p53‐expressing senescent liver satellite cells release IFN‐γ and IL‐6, which in turn skew the polarization of resident Kupffer macrophages and freshly infiltrated macrophages toward the pro‐inflammatory M1 phenotype (Lujambio et al ., 2013). These M1 macrophages can then rapidly eliminate senescent liver satellite cells within the injured tissue.…”

Section: Cellular Senescence and Immunity In Tissue Homeostasismentioning

confidence: 99%

“…These M1 macrophages can then rapidly eliminate senescent liver satellite cells within the injured tissue. In contrast, the loss of p53 in senescent liver satellite cells results in IL‐4 production, switching macrophage polarization toward the pro‐survival and pro‐angiogenic M2 phenotype (Lujambio et al ., 2013). …”

Section: Cellular Senescence and Immunity In Tissue Homeostasismentioning

confidence: 99%

Cellular senescence impact on immune cell fate and function

et al. 2016

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SummaryCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.

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“…Indeed, recent reports suggest that p53 may indeed have such a role to play in TAM biology. 19,20 A low concentration of endotoxin triggers tolerance, which involves the reprogramming of macrophages. 21 Prior exposure to endotoxin can be an evolutionary advantage because it triggers a selective shutdown of the production of proinflammatory cytokines (from M1 macrophages), which cause tissue damage and preserves the generation of protective antiinflammatory mediators (from M2 macrophages).…”

Section: Figure 7 (Continued)mentioning

confidence: 99%

A unique role for p53 in the regulation of M2 macrophage polarization

Li¹,

et al. 2014

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P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing. 1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This 'plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype. 2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years.P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair. 3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer, 4 the role of p53 in inflammation is not clear. Macrophages from p53 − / − mice produce increased quantities of proinflammatory cytokines in response to LPS, 5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53 − ...

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Non-Cell-Autonomous Tumor Suppression by p53

Cited by 632 publications

References 48 publications

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Senescent cells expose and secrete an oxidized form of membrane-bound vimentin as revealed by a natural polyreactive antibody

Cellular senescence impact on immune cell fate and function

A unique role for p53 in the regulation of M2 macrophage polarization

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