Dual role of TMS1/ASC in death receptor signaling

Parsons, Matthew S.; Vertino, Paula M.

doi:10.1038/sj.onc.1209684

Cited by 23 publications

(33 citation statements)

References 63 publications

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“…Previous studies have shown that TMS1 is up-regulated in response to inflammatory stimuli, such as interleukin 1␤, interferon-␥, and lipopolysaccharide in macrophage (15,16), although the mechanism of that regulation has not been determined. In breast epithelial cells, TMS1 is up-regulated in response to stress stimuli, including proinflammatory cytokines, such as TNF␣ and TRAIL (17), and in response to detachment from the substratum (20). Whereas the former is dependent on the NF-B and c-Jun NH 2 -terminal kinase (JNK) pathways; up-regulation in response to detachment was independent of these pathways (20).…”

Section: Discussionmentioning

confidence: 99%

“…However, subsequent studies suggest that the regulation of TMS1 by p53 may be more complex. For example, although treatment of breast epithelial cells or breast cancer cells wild-type for p53 with DNA damaging agents leads to a modest increase in TMS1 protein expression (17), this up-regulation appeared to be independent of p53 in siRNA experiments, and similar treatments had little impact on the activity of TMS1 promoter fragments containing the putative p53 element in reporter assays. 5 The data presented here indicate that the GABP␣/␤1 complex plays a role in the regulation of TMS1 and is necessary to maintain basal expression at the TMS1 locus.…”

Section: Discussionmentioning

confidence: 99%

“…Oligomerization of TMS1/ASC induced by interaction with intracellular pathogen sensors mediates the assembly of a multiprotein complex that ultimately leads to the activation of caspase-1, maturation and release of the cytokines interleukin-1␤ and interleukin-18, and the induction of "pyroptosis," a proinflammatory form of programmed cell death (15,16). TMS1/ASC is also widely expressed in epithelial cells, where it is up-regulated in response to cell stress stimuli, such as the death ligands TNF␣ and TRAIL (17). Overexpression or forced oligomerization of TMS1 in epithelial cells promotes a caspase-8-dependent cell death (17)(18)(19).…”

mentioning

confidence: 99%

“…TMS1/ASC is also widely expressed in epithelial cells, where it is up-regulated in response to cell stress stimuli, such as the death ligands TNF␣ and TRAIL (17). Overexpression or forced oligomerization of TMS1 in epithelial cells promotes a caspase-8-dependent cell death (17)(18)(19). Recently, we showed that TMS1 plays a critical role in anoikis, or apoptosis induced in response to the loss of integrin-mediated contacts with the substratum, in breast epithelial cells (20).…”

mentioning

confidence: 99%

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Methylation-sensitive Regulation of TMS1/ASC by the Ets Factor, GA-binding Protein-α

Lucas

Crider

Powell

et al. 2009

Journal of Biological Chemistry

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Epigenetic silencing involving the aberrant DNA methylation of promoter-associated CpG islands is one mechanism leading to the inactivation of tumor suppressor genes in human cancers. However, the molecular mechanisms underlying this event remains poorly understood. TMS1/ASC is a novel proapoptotic signaling factor that is subject to epigenetic silencing in human breast and other cancers. The TMS1 promoter is embedded within a CpG island that is unmethylated in normal cells and is spanned by three DNase I-hypersensitive sites (HS). Silencing of TMS1 in cancer cells is accompanied by local alterations in histone modification, remodeling of the HS, and hypermethylation of DNA. In this study, we probed the functional significance of the CpG island-specific HS. We identified a methylation-sensitive complex that bound a 55-bp intronic element corresponding to HS2. Affinity chromatography and mass spectrometry identified a component of this complex to be the GA-binding protein (GABP) ␣. Supershift analysis indicated that the GABP␣ binding partner, GABP␤1, was also present in the complex. The HS2 element conferred a 3-fold enhancement in TMS1 promoter activity, which was dependent on both intact tandem ets binding sites and the presence of GABP␣/␤1 in trans. GABP␣ was selectively enriched at HS2 in human cells, and its occupancy was inversely correlated with CpG island methylation. Down-regulation of GABP␣ led to a concomitant decrease in TMS1 expression. These data indicate that the intronic HS2 element acts in cis to maintain transcriptional competency at the TMS1 locus and that this activity is mediated by the ets transcription factor, GABP␣.Methylation of DNA in the human genome is tightly controlled during development by the action of DNA methyltransferases. DNA methyltransferases catalyze the transfer of a methyl group from S-adenosylmethionine to the carbon-5 position of cytosine in the dinucleotide 5Ј-CpG-3Ј. This epigenetic mark is copied after DNA synthesis, providing a heritable memory of transcriptional status. Overall, CpG dinucleotides are depleted in the human genome except in CpG islands (1). CpG islands are ϳ200 bp to several kb in length and are found mainly in the 5Ј-regions of 70% of human genes (2). Most CpG dinucleotides in the genome are heavily methylated whereas, in contrast, the CpG sites in the CpG islands, especially those associated with gene promoters, are usually unmethylated. Aberrant methylation of such CpG islands is associated with inappropriate gene silencing and has been implicated in the inactivation of tumor suppressor genes in human cancers.At present, the mechanisms underlying cancer-associated CpG island methylation are unknown. There are at least two mechanisms in which aberrant DNA methylation is thought to contribute to stable gene repression. DNA methylation can affect gene expression through its affects on local chromatin structure. Methylated DNA is recognized by methyl-CpGbinding domain proteins, which are components of repressor complexes that contain histone deacetylas...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Methylation-sensitive Regulation of TMS1/ASC by the Ets Factor, GA-binding Protein-α

Lucas

Crider

Powell

et al. 2009

Journal of Biological Chemistry

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“…It is specifically expressed in leukocytes and can be induced interinsically by p53 expression (Wright and Deshmukh, 2006) and extrinsically by LPS and TNF-α (Stehlik et al, 2003). TMS1 was shown to bind and activate both caspase-1 (Stehlik et al, 2003) and caspase-8 (Masumoto et al, 2003;Parsons and Vertino, 2006). The lack of TMS1 expression was suggested to impart cells with increased resistance to apoptotic stimuli through both intrinsic and extrinsic pathways (Wright and Deshmukh, 2006).…”

Section: Dna Hypermethylation Of Cell Cycle and Apoptotic Genes In Pementioning

confidence: 99%

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Bodoor

Haddad

Alkhateeb

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Aberrant DNA methylation of tumor suppressor genes has been reported in all major types of leukemia with potential involvement in the inactivation of regulatory cell cycle and apoptosis genes. However, most of the previous reports did not show the extent of concurrent methylation of multiple genes in the four leukemia types. Here, we analyzed six key genes (p14, p15, p16, p53, DAPK and TMS1) for DNA methylation using methylation specific PCR to analyze peripheral blood of 78 leukemia patients (24 CML, 25 CLL, 12 AML, and 17 ALL) and 24 healthy volunteers. In CML, methylation was detected for p15 (11%), p16 (9%), p53 (23%) and DAPK (23%), in CLL, p14 (25%), p15 (19%), p16 (12%), p53 (17%) and DAPK (36%), in AML, p14 (8%), p15 (45%), p53 (9%) and DAPK (17%) and in ALL, p15 (14%), p16 (8%), and p53 (8%). This study highlighted an essential role of DAPK methylation in chronic leukemia in contrast to p15 methylation in the acute cases, whereas TMS1 hypermethylation was absent in all cases. Furthermore, hypermethylation of multiple genes per patient was observed, with obvious selectiveness in the 9p21 chromosomal region genes (p14, p15 and p16). Interestingly, methylation of p15 increased the risk of methylation in p53, and vice versa, by five folds (p=0.03) indicating possible synergistic epigenetic disruption of different phases of the cell cycle or between the cell cycle and apoptosis. The investigation of multiple relationships between methylated genes might shed light on tumor specific inactivation of the cell cycle and apoptotic pathways.

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Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus

Webb

Wren

Jeffries

et al. 2009

Arthritis & Rheumatism

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Objective. Both genetic and epigenetic factors play an important role in the pathogenesis of lupus. The aim of this study was to examine methyl-CpG-binding protein 2 gene (MECP2) polymorphisms in a large cohort of patients with lupus and control subjects, and to determine the functional consequences of the lupusassociated MECP2 haplotype.Methods. We genotyped 18 single-nucleotide polymorphisms within MECP2, located on chromosome Xq28, in a large cohort of patients with lupus and control subjects of European descent. We studied the functional effects of the lupus-associated MECP2 hap-

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Dual role of TMS1/ASC in death receptor signaling

Cited by 23 publications

References 63 publications

Methylation-sensitive Regulation of TMS1/ASC by the Ets Factor, GA-binding Protein-α

Methylation-sensitive Regulation of TMS1/ASC by the Ets Factor, GA-binding Protein-α

DNA Hypermethylation of Cell Cycle (p15 and p16) and Apoptotic (p14, p53, DAPK and TMS1) Genes in Peripheral Blood of Leukemia Patients

Variants within MECP2, a key transcription regulator, are associated with increased susceptibility to lupus and differential gene expression in patients with systemic lupus erythematosus

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