The Alzheimer's disease-associated TREM2 gene is regulated by p53 tumor suppressor protein

Zajkowicz, Artur; Gdowicz-Kłosok, Agnieszka; Krześniak, Małgorzata; Janus, Patryk; Łasut, Barbara; Rusin, Marek

doi:10.1016/j.neulet.2018.05.037

Cited by 21 publications

(37 citation statements)

References 18 publications

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“…Interleukin-18 promotes the release of IFN-γ by NK-cells and T-cells [6]. Based on our previously reported observations [1,2] and recent work by other investigators [5,7], we hypothesized that activation of p53 by A + N co-treatment induces pyroptosis of A549 cells. We started this study with testing of this hypothesis.…”

Section: Introductionmentioning

confidence: 87%

“…The luciferase reporter assay was performed as described recently [2]. In short, U-2 OS cells were co-transfected using FuGene6 (Promega) with a combination of reporter vector, encoding firefly luciferase under the control of NLRX1 or NLRP1 regulatory elements (wild type or mutant), and expression vector pC53-SN3, encoding wild-type p53 or pC53-SCX3 encoding Val143Ala p53 mutant (a gift from Dr. Bert Vogelstein and Dr. Kenneth W. Kinzler from Johns Hopkins University, Baltimore, MD, USA) [9].…”

Section: Molecular Cloning Site-directed Mutagenesis and Luciferase mentioning

confidence: 99%

“…Actinomycin D and nutlin-3a (A + N) synergistically activate the p53 pathway in various cell lines [1,2]. Actinomycin D is an anticancer drug, which at low concentration inhibits RNA polymerase I (RNA Pol I).…”

Section: Introductionmentioning

confidence: 99%

“…The phosphorylation of Ser46 is difficult to observe in the presence of actinomycin D and is undetectable in the presence of nutlin-3a. However, when both substances are applied together, the status of phospho-Ser46 p53 reaches very high levels [1,2]. The phosphorylation of Ser46 is considered a marker of activated p53, which efficiently stimulates the expression of proapoptotic genes [4].…”

Section: Introductionmentioning

confidence: 99%

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Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

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Section: Introductionmentioning

confidence: 87%

Section: Molecular Cloning Site-directed Mutagenesis and Luciferase mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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“…The most significant rTg4510-associated differentially-expressed transcript is Car4, which encodes carbonic anhydrase 4 ( Supplementary Figure 6a, upregulated in TG mice, Wald statistic = 8.36, log2 fold change = 1.11, FDR = 2.41E-13). Other differentially expressed genes in mice carrying the rTg4510 transgene include Gpr17, which encodes the G protein-coupled receptor 17 that is involved in regulating oligodendrocyte differentiation and maturation 31 (Supplementary Figure 6b, downregulated in TG mice, Wald statistic = -6.73, log2 fold change = -0.62, FDR = 5.11E-08); Blnk, which encodes a cytoplasmic linker protein that plays a critical role in B cell development and is involved in the TREM2 activation pathway 32 (Supplementary Figure 6c, upregulated in TG mice, Wald statistic = 6.48, log2 fold change = 0.80, FDR = 2.12E-07); and Hspa5 (also known as Bip or Grp78), which encodes a member of the heat shock protein 70 (HSP70) family that is localized in the lumen of the endoplasmic reticulum (ER) and involved in the folding and assembly of proteins, and has been previously implicated in neuroprotection and AD 33,34 (Supplementary Figure 6d, downregulated in TG mice, Wald statistic = -6.16, log2 fold change = -0.58, FDR = 1.37E-06). Hierarchical clustering of individual mice based on expression levels for genotype-associated transcripts robustly discriminates between rTg4510 and WT groups (Figure 2a).…”

Section: The Rtg4510 Model Of Tau Pathology Is Characterized By Widesmentioning

confidence: 99%

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

Castanho

Hannon

et al. 2019

Preprint

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The onset and progression of Alzheimer's disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of β-amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systemslevel analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.3

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Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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The Alzheimer's disease-associated TREM2 gene is regulated by p53 tumor suppressor protein

Cited by 21 publications

References 18 publications

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

Molecular crosstalk between cancer and neurodegenerative diseases

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