Disease relevance of PYCARD

• BACKGROUND: The aim of this study was to investigate the methylation status of apoptosis-associated speck-like protein containing a CARD (ASC; TMS1; PYCARD) in prostate cancer cell lines and human tissues and to determine if those findings correlate with the clinicopathological features of prostate cancer [1].
• We also show that TMS1 is aberrantly methylated and silenced in human breast cancer cells [2].
• The gene introduction of ASC may thus restore such chemosensitivity, and this modality may therefore be a useful new treatment strategy for colorectal cancer [3].
• When expressed in colon cancer cells, in which ASC is absent due to methylation, ASC was found to enhance the chemosensitivity in a p53-dependent manner [3].
• Epigenetic inactivation of TMS1/ASC in ovarian cancer [4].

Psychiatry related information on PYCARD

• Despite the large overlap of these two scales, they measure somewhat different aspects of "Panic-Fear". The ASC measures a situational response (state variable) to breathing difficulties, while the MMPI measures a more stable, diffuse, and global personality characteristic (trait variable) [5].
• Parents help ease separation anxiety in ASC (ambulatory surgery center) [6].

High impact information on PYCARD

• Here we show that wild-type Francisella, which reach the cytosol, but not Francisella mutants that remain localized to the vacuole, induced a host defense response in macrophages, which is dependent on caspase-1 and the death-fold containing adaptor protein ASC [7].
• Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis [7].
• The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways [8].
• Blocking of endogenous ASC expression by small-interfering RNA (siRNA) reduced the apoptotic response and inhibited translocation of Bax to mitochondria in response to p53 or genotoxic insult, suggesting that ASC is required to translocate Bax to the mitochondria [9].
• When ectopically expressed, ASC interacted directly with Bax, colocalized with Bax to the mitochondria, induced cytochrome c release with a significant reduction of mitochondrial membrane potential and resulted in the activation of caspase-9, -2 and -3 [9].

Chemical compound and disease context of PYCARD

• Treatment with demethylating agent 5-aza-2'-deoxycytidine resulted in both demethylation of the ASC gene and the upregulation of ASC expression in the methylation positive melanoma cell lines [10].
• We characterized methylation patterns in melanoma cell lines by using bisulfite genomic sequencing, and found that the degree of aberrant methylation correlated with the level of reductive ASC expression [10].
• Treatment of MDAPCa2b prostate cancer cells with the methylation inhibitors 5-aza-2-deoxycitidine and Zebularine reactivated expression of ASC [1].
• Comment on Rice ASC, Maton S, the Postherpetic Neuralgia Study Group (UK), gabapentin in postherpetic neuralgia: a randomized, double blind, placebo-controlled study [11].
• Previously we reported that phorbol esters regulate hepatoma System ASC/B(0)-mediated glutamine uptake and cell growth [12].

Biological context of PYCARD

• Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/target of methylation-induced silencing/PYCARD represents one of only two proteins encoded in the human genome that contains a caspase recruitment domain (CARD) together with a pyrin, AIM, ASC, and death domain-like (PAAD)/PYRIN/DAPIN domain [13].
• Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis [14].
• These results are the first to indicate that caspase-8 plays an important role in the ASC-mediated NF-kappaB activation, and that the ASC-mediated NF-kappaB activation actually induces physiologically relevant gene expression [15].
• Exon 1 of pyrin and exon 1 of ASC show 42% sequence similarity and resemble death domain-related structures in modeling studies [14].
• In the present paper, we describe characterization of human PAAD-only protein-1 (POP1)/ASC2, which is highly homologous with the PAAD domain of ASC, and which probably originated by gene duplication on chromosome 16 [16].

Anatomical context of PYCARD

• Using pyrin as a "bait" to probe a yeast two-hybrid library made from neutrophil cDNA, we isolated apoptotic speck protein containing a caspase recruitment domain (CARD) (ASC), a proapoptotic protein that induces the formation of large cytosolic "specks" in transfected cells [14].
• We found that when HeLa cells are transfected with ASC, specks are formed [14].
• We show here that ASC binds by its CARD to procaspase-1 and to adapter proteins involved in caspase-1 activation, thereby regulating cytokine pro-IL-1beta activation by this protease in THP-1 monocytes [13].
• ASC mRNA levels were comparable in RA and OA tissue, FLS, and macrophages, and were depressed by TNFalpha in macrophages [17].
• Caspase-8 deficiency rescued mouse fibroblasts from apoptosis induced by ASC oligomerization [18].

Associations of PYCARD with chemical compounds

• The role of vitamin C (ascorbic acid, ASC), a known modulator of the cellular redox status, in regulating mitotic entry was investigated in this study [19].
• RNA expression was restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMS1 transcript [20].
• Intron 9 carries a retrotransposon-like element, Tms1, which might be responsible for downstream deletion events in which a heptanucleotide, ATTAGCT, might have been involved [21].
• In the colon, ASC was detected in mature epithelial cells facing the luminal side rather than immature cells located deeper in the crypts [22].
• Methylation of the TMS1 gene was detected using methylation-specific PCR followed by bisulfite-modification of DNA [23].
• Induction of TMS1/ASC by TNFalpha was blocked by co-expression of a dominant negative IkappaBalpha, small interfering RNA-mediated knockdown of RelA/p65, or concurrent treatment with SP600125, indicating a requirement for the nuclear factor-kappaB (NF-kappaB) and jun kinase signaling pathways [24].

Physical interactions of PYCARD

• In the absence of stimuli, wild-type cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins [25].
• The CARD domain of CARD12 interacts selectively with the CARD domain of ASC, a recently identified proapoptotic protein [26].
• Phosphorylation mutants of p53 show differential complex formation with putative dehydrogenase Tms1 of fission yeast [27].

Co-localisations of PYCARD

• Immunofluorescence studies show that pyrin co-localizes with ASC in specks [14].

Regulatory relationships of PYCARD

• In addition, PYPAF1 induces caspase-1-dependent cytokine processing when co-expressed with ASC [28].
• In gene transfer experiments PAN1 enhances caspase-1 activation and IL-1beta secretion in collaboration with ASC [29].
• ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions [30].

Other interactions of PYCARD

• We also show here that PAN1 binds via its PYRIN domain to ASC, an adapter protein involved in caspase-1 activation [29].
• This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members [31].
• However, expression of ASC uniformly interferes with caspase-1 activation and IL-1beta secretion induced by proinflammatory stimuli such as LPS and TNF, suggesting pathway competition [13].
• We demonstrate that POP1/ASC2 associates with ASC via PAAD-PAAD interactions and modulates NF-kappa B and pro-caspase-1 regulation by this adapter protein [16].
• Moreover, ASC also recruits procaspase-1 into ASC-formed cytosolic specks, separating it from Cardiak [13].

Analytical, diagnostic and therapeutic context of PYCARD

• ASC enhances IL-1beta secretion into the cell culture supernatants, at low concentrations, while suppressing at high concentrations [13].
• An inactivation of ASC might thus cause resistance to chemotherapy, and if this is the case, then the expression of ASC would restore the chemosensitivity [3].
• To investigate whether ASC silencing in melanoma is involved in aberrant methylation, methylation specific PCR was carried out [10].
• DNA methylation was confirmed by sequence analysis and the methylation status correlated inversely with TMS1 RNA expression in 18 cell lines tested [20].
• In our present study, ASC expression was examined in 12 melanoma cell lines by Western blot analysis and in 18 benign melanocytic nevi and 32 melanoma tissues by immunohistochemical staining [10].

References