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Xiaotian Chang - One of the best experts on this subject based on the ideXlab platform.
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stimulation of dc cik with PADI4 protein can significantly elevate the therapeutic efficiency in esophageal cancer
Clinical & Developmental Immunology, 2019Co-Authors: Yingying Zheng, Junyi Tang, Dawei Wang, Shutong Li, Xiaotian ChangAbstract:Background. PADI4 has extensive expression in many tumors. This study applied PADI4 as a tumor marker to stimulate DC- (dendritic cell-) CIK (cytokine-induced killer), an immunotherapy approach. Methods. A PADI4 expression plasmid was transfected into EC-originating ECA-109 cells. PADI4 gene was also inserted into a prokaryotic expression vector to produce recombinant protein. Lysate from PADI4-overexpressing cells or the purified recombinant PADI4 protein was used to load DCs, and the cells were then coincubated with CIK cells. DC and CIK cell phenotypes were determined using flow cytometry. The proliferation and viability of CIK cells were analyzed using trypan blue staining. The cytotoxic effect of DC-CIK cells on cultured ECA-109 cells was determined using CCK8 assays. Tumor-bearing mice were prepared by injection of ECA-109 cells. DC-CIK cells stimulated with lysate from PADI4-overexpressing cells or the PADI4 recombinant protein were injected into the tumor-bearing mice. The tumor growth was measured with magnetic resonance imaging (MRI). Results. Following incubation with lysate from PADI4-overexpressing cells, the ratio of CD40
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PADI4 stimulates esophageal squamous cell carcinoma tumor growth and up regulates ca9 expression
Molecular Carcinogenesis, 2019Co-Authors: Junyi Tang, Chang Li, Guangbo Pu, Dongxia Yang, Xiaotian ChangAbstract:An increasing amount of evidence indicates that peptidylarginine deiminase isoform 4 (PADI4) plays an important role in tumorigenesis. However, the effects of PADI4 on tumor‐bearing mice are unknown, and no studies have investigated this tumorigenic pathway in an animal model. In the present study, ECA109 cells originating from esophageal squamous cell carcinoma (ESCC) were transfected with PADI4‐expressing lentivirus and were injected into BALB/c nude mice. Tumor size and weight were significantly increased in the mouse tumors established with PADI4‐overexpressing ECA109 cells. PCR array analysis revealed increased CA9 expression in ECA109 cells transfected with a PADI4‐expressing plasmid, while decreased CA9 expression levels were detected in cells transfected with anti‐PADI4 siRNA. Furthermore, up‐regulation of CA9 expression was detected in mouse tumors established with PADI4‐overexpressing cells. Immunohistochemistry detected the increased expression and co‐localization of PADI4 and CA9 in ESCC tissues compared with adjacent non‐tumor tissues and normal tissue controls. These results were verified using Western blotting. Cell proliferation significantly increased or decreased in ECA109 and EC9706 (another ESCC‐originating cell line) cells transfected with a PADI4‐expressing plasmid or anti‐PADI4 siRNA, respectively. The above findings suggest that increased PADI4 expression in ESCC stimulates tumor growth and up‐regulates CA9 expression, which is known to promote metastatic properties in tumor cells.
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PADI4 has genetic susceptibility to gastric carcinoma and upregulates cxcr2 krt14 and tnf α expression levels
Oncotarget, 2016Co-Authors: Ya-bing Zheng, Chang Li, Gang Zhao, Bing Xu, Xiaoqian Zhang, Xiaotian ChangAbstract:// Yabing Zheng 1, * , Gang Zhao 2, * , Bing Xu 1 , Chunyan Liu 1 , Chang Li 3 , Xiaoqian Zhang 4 , Xiaotian Chang 1 1 Medical Research Center of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, P. R. China 2 Emergency Surgery Department of Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, P. R. China 3 Pathological Department of Tengzhou People’s Central Hospital, Tengzhou, Shandong, P. R. China 4 Clinical Laboratory of PKUCare Luzhong Hospital, Zibo, Shandong, P. R. China * These authors have contributed equally to this work Correspondence to: Xiaotian Chang, email: changxt@126.com Keywords: peptidyl deiminase (PAD), peptidyl deiminase isoform 4 (PADI4), CXCR2, KRT14, TNF-α Received: October 18, 2015 Accepted: August 08, 2016 Published: August 19, 2016 ABSTRACT PADI4 (peptidyl deiminase isoform 4) is overexpressed in many tumor tissues and converts arginine residues to citrulline residues. This study used an Illumina SNP microarray and a TaqMan assay to determine the possible association of the PADI4 gene with various tumor risks. Both genotyping methods demonstrated significant associations between the tag SNPs rs1635566 and rs882537 in the PADI4 locus with gastric carcinoma in two independent cohorts. Based on this genotyping result, we used the Cancer Pathway Finder, p53 Signaling, Signal Transduction and Tumor Metastasis PCR arrays to investigate the tumorigenic pathway of PADI4 in MNK-45 cells derived from gastric carcinoma. We detected significantly decreased expression levels of CXCR2, KRT14 and TNF-α in MNK-45 cells that were treated with anti-PADI4 siRNA. We also detected increased expression of these three genes in MNK-45 cells transfected with a pcDNA3.1 plasmid overexpressing PADI4. A highly similar result was also obtained for SGC 7901 cells, which also originate from gastric carcinoma. Our result indicates that the PADI4 gene has genetic susceptibility in gastric carcinoma. PADI4 contributes to gastric tumorigenesis by upregulating CXCR2, KRT14 and TNF-α expression, which are well known to activate angiogenesis, cell proliferation, cell migration and the immune microenvironment in tumors.
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The role of peptidylarginine deiminase 4 in ovarian cancer cell tumorigenesis and invasion
Tumor Biology, 2015Co-Authors: Jing Zhou, Shan Zhao, Ya-bing Zheng, Hongtao Lv, Fengnian Rong, Xiaotian ChangAbstract:Peptidylarginine deiminase 4 (PADI4) is an enzyme that converts both histone arginine and mono-methyl arginine residues to citrulline, and it has been detected in various subtypes of ovarian cancer. However, the mechanism of action of PADI4 in ovarian carcinogenesis remains unknown. To examine the function of PADI4, we transfected two ovarian cancer cell lines, wild-type p53 A2780 and p53-null SKOV3, with PADI4-siRNA and negative control siRNA. The proliferation of both A2780 and SKOV3 cells decreased significantly following PADI4-siRNA treatment (P A2780 0.05). PCR arrays of A2780 cells treated with PADI4-siRNA revealed the up-regulated expression of six genes, including cell death-inducing DFFA-like effector a (CIDEA) and tumor necrosis factor receptor superfamily member 9 (TNFRSF9), and the down-regulation of seven genes, including integrin beta 3 (ITGB3) and BCL2-antagonist/killer 1 (BAK1). These results suggest an important role for PADI4 in the p53 pathway and the regulation of the proliferation, apoptosis, invasion and migration of ovarian cancer cells. Our study also demonstrated that PADI4 contributes to tumor metastasis by regulating the gene expression of insulin-like growth factor 1 (IGF1) and WAS/WASL-interacting protein family member 1 (WIPF1).
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investigating the pathogenic role of PADI4 in oesophageal cancer
International Journal of Biological Sciences, 2011Co-Authors: Xiaotian Chang, Kehua Fang, Lin WangAbstract:PADI4 post-translationally converts peptidylarginine to citrulline. PADI4 can disrupt the apoptotic process via the citrullination of histone H3 in the promoter of p53-target genes. The current study focused on PADI4 expression in various subtypes of oesophageal carcinoma (EC) by immunohistochemistry, western blotting and real time PCR. The study also investigated the effect of bile acid deoxycholate (DCA) on PADI4 expression in Eca-109 cells that originated from EC. Apoptosis and DCA-induced toxicity were analyzed by TUNEL, MTT assay and flow cytometry. Additionally, the present study investigated the correlation between single nucleotide polymorphism (SNP) in PADI4 gene and EC risk in Chinese population using Illumina GoldenGate assay. Compared with paraneoplastic tissues, the transcriptional and translational levels of PADI4 were significantly elevated in oesophageal squamous cell carcinoma (ESCC, n=9) and oesophageal adenocarcinoma (EAC, n=5) tissues. Immunolabeling detected expression of PADI4 in ESCC tissues (98.56%, n=139), EAC samples (87.5%, n=16) and oesophageal small cell undifferentiated carcinoma (91.7%, n=12) but not in normal tissues (0%, n=16). Furthermore, PADI4 levels is positively correlated with the pathological classification of ESCC (p=0.009). PADI4 expression levels were consistent with the number of apoptotic cells in the induced Eca-109 cells. rs10437048 [OR= 0.012831; 95% CI, 0.001746~0.094278; p=1.556×10 -12 ] were significantly associated with decreased risk of EC, whereas rs41265997 [OR=12.7; 95% CI, 0.857077~33.207214; p=3.896×10 -8 ] were significantly associated with increased risk of EC. rs41265997 in exon 3 of PADI4 gene is non-synonymous and converts ACG to ATG resulting in a threonine /methionine conversion at position 274 of the protein. Haplotypes GC that carries the variant alleles for rs2501796 and rs2477134 was significantly associated with increased risk of EC (frequency=0.085, p=0.0256, OR=2.7). The results suggest that PADI4 expression is related to the tumorigenic process of EC and the DCA-induced apoptosis. The PADI4 gene may be a valid EC susceptibility gene.
Koichi Matsuda - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 036 citrullinome analysis identifies the role of PADI4 in regulating rna processing and tumor immunogenicity
Cancer Research, 2017Co-Authors: Chizu Tanikawa, Koichi MatsudaAbstract:Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in PADI4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy. Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-036. doi:10.1158/1538-7445.AM2017-LB-036
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abstract 1562 proteomic analysis of citrullinated targets regulated by the p53 PADI4 pathway
Cancer Research, 2014Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koji Ueda, Hidewaki Nakagawa, Koichi MatsudaAbstract:We recently reported that p53 regulates protein citrullination through the transcriptional regulation of PADI4 that converts an arginine residue in proteins to a citrulline residue. In response to DNA damage, p53-PADI4 pathway induces citrullination of NPM1, Histone H4, and Lamin C, and subsequently promotes apoptotic pathway. To verify the clinical significance of PADI4 in human carcinogenesis, we screened the mutation of PADI4 in hepatocellular carcinoma and found three non-synonymous mutations among 104 cancer tissues (2.9%). Then we evaluated these three mutations as well as 8 somatic mutations reported by ICGC or COMP projects. We found that 8 among 11 mutations remarkably inhibited the enzymatic activity of PADI4 protein. To identify novel PADI4 substrates, we conducted proteome analysis using HEK293T cells ectopically transfected with wild type or mutant PADI4 expressing plasmid. Among more than 10000 peptides identified by the liquid chromatography MS/MS analysis, 265 peptides (2.2%) were citrullinated in PADI4-introduced cells, while less than 0.4% of total peptides were citrullinated in control or mock transfected cells. Pathway analysis revealed that RNA binding proteins such as hnRNPs are dominantly citrullinated by PADI4, indicating that possible role of protein citrullination in RNA processing. Citation Format: Chizu Tanikawa, Koji Ueda, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Proteomic analysis of citrullinated targets regulated by the p53-PADI4 pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2014-1562
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corrigendum regulation of histone modification and chromatin structure by the p53 PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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abstract 5015 regulation of histone modification and chromatin structure by p53 PADI4 pathway
Cancer Research, 2012Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koichi MatsudaAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Histone proteins are modified in response to various external signals, however their mechanisms are still not fully understood. We here report in vivo and in vitro citrullination of arginine 3 residue of histone H4 (H4R3) in response to DNA damage through the p53-PADI4 pathway. We also observed DNA damage-induced citrullination of lamin C through the p53-PADI4 pathway. Citrullinated H4R3 (cit-H4R3) and citrullinated lamin C are located around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 led to chromatin decondensation and promoted DNA cleavage, while PADI4-/- mice exhibited resistance to radiation-induced apoptosis in the thymus. We also found loss of function mutations of the PADI4 gene in several cancer cell lines. Furthermore, the level of cit-H4R3 was negatively correlated with that of p53 protein in cancer cells and with tumor size in non-small cell lung cancer tissues. Our findings reveal that citrullination of H4R3 would be an “apoptotic histone code” to detect damaged cells and induce nuclear fragmentation, which plays a crucial role in carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5015. doi:1538-7445.AM2012-5015
Chizu Tanikawa - One of the best experts on this subject based on the ideXlab platform.
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abstract lb 036 citrullinome analysis identifies the role of PADI4 in regulating rna processing and tumor immunogenicity
Cancer Research, 2017Co-Authors: Chizu Tanikawa, Koichi MatsudaAbstract:Recent proteome analyses have provided a comprehensive overview of various posttranscriptional modifications (PTM); however, PTMs involving protein citrullination remain unclear. Thus, we performed a proteomic analysis of citrullinated proteins and identified more than 100 PADI4 substrates, the majority of which are related to RNA processing and protein translation. Citrullination of RBMX (RNA binding motif protein, X-linked) inhibited the interaction with other hnRNP family members. RNA sequence analyses revealed altered splicing patterns in more than 300 genes in bone marrow cells in PADI4-/- mice. Approximately one-fifth of the PADI4 substrates contained an RG/RGG motif, and citrullination by PADI4 competitively inhibited the methylation of the RGG motif in FET proteins (EWS and TAF15). In addition, PADI4-mediated citrullination inhibited the aggregation of TAF15 proteins, which is a frequently-observed feature in neurodegenerative diseases, such as ALS. An antibody against citrullinated RGG motifs was observed in 11.5% (27 among 234) of serum samples from patients with HCV-related hepatocellular carcinoma, and female patients with high serum antibody exhibited poor prognosis. Our findings imply that PADI4-mediated citrullination plays a key role in RNA processing, protein aggregation and tumor immunogenicity, and suggest that PADI4 activation has potential therapeutic implications for neurodegenerative disease and cancer immunotherapy. Citation Format: Chizu Tanikawa, Koichi Matsuda. Citrullinome analysis identifies the role of PADI4 in regulating RNA processing and tumor immunogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-036. doi:10.1158/1538-7445.AM2017-LB-036
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abstract 1562 proteomic analysis of citrullinated targets regulated by the p53 PADI4 pathway
Cancer Research, 2014Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koji Ueda, Hidewaki Nakagawa, Koichi MatsudaAbstract:We recently reported that p53 regulates protein citrullination through the transcriptional regulation of PADI4 that converts an arginine residue in proteins to a citrulline residue. In response to DNA damage, p53-PADI4 pathway induces citrullination of NPM1, Histone H4, and Lamin C, and subsequently promotes apoptotic pathway. To verify the clinical significance of PADI4 in human carcinogenesis, we screened the mutation of PADI4 in hepatocellular carcinoma and found three non-synonymous mutations among 104 cancer tissues (2.9%). Then we evaluated these three mutations as well as 8 somatic mutations reported by ICGC or COMP projects. We found that 8 among 11 mutations remarkably inhibited the enzymatic activity of PADI4 protein. To identify novel PADI4 substrates, we conducted proteome analysis using HEK293T cells ectopically transfected with wild type or mutant PADI4 expressing plasmid. Among more than 10000 peptides identified by the liquid chromatography MS/MS analysis, 265 peptides (2.2%) were citrullinated in PADI4-introduced cells, while less than 0.4% of total peptides were citrullinated in control or mock transfected cells. Pathway analysis revealed that RNA binding proteins such as hnRNPs are dominantly citrullinated by PADI4, indicating that possible role of protein citrullination in RNA processing. Citation Format: Chizu Tanikawa, Koji Ueda, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Proteomic analysis of citrullinated targets regulated by the p53-PADI4 pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2014-1562
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corrigendum regulation of histone modification and chromatin structure by the p53 PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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abstract 5015 regulation of histone modification and chromatin structure by p53 PADI4 pathway
Cancer Research, 2012Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koichi MatsudaAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Histone proteins are modified in response to various external signals, however their mechanisms are still not fully understood. We here report in vivo and in vitro citrullination of arginine 3 residue of histone H4 (H4R3) in response to DNA damage through the p53-PADI4 pathway. We also observed DNA damage-induced citrullination of lamin C through the p53-PADI4 pathway. Citrullinated H4R3 (cit-H4R3) and citrullinated lamin C are located around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 led to chromatin decondensation and promoted DNA cleavage, while PADI4-/- mice exhibited resistance to radiation-induced apoptosis in the thymus. We also found loss of function mutations of the PADI4 gene in several cancer cell lines. Furthermore, the level of cit-H4R3 was negatively correlated with that of p53 protein in cancer cells and with tumor size in non-small cell lung cancer tissues. Our findings reveal that citrullination of H4R3 would be an “apoptotic histone code” to detect damaged cells and induce nuclear fragmentation, which plays a crucial role in carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5015. doi:1538-7445.AM2012-5015
Yusuke Nakamura - One of the best experts on this subject based on the ideXlab platform.
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abstract 1562 proteomic analysis of citrullinated targets regulated by the p53 PADI4 pathway
Cancer Research, 2014Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koji Ueda, Hidewaki Nakagawa, Koichi MatsudaAbstract:We recently reported that p53 regulates protein citrullination through the transcriptional regulation of PADI4 that converts an arginine residue in proteins to a citrulline residue. In response to DNA damage, p53-PADI4 pathway induces citrullination of NPM1, Histone H4, and Lamin C, and subsequently promotes apoptotic pathway. To verify the clinical significance of PADI4 in human carcinogenesis, we screened the mutation of PADI4 in hepatocellular carcinoma and found three non-synonymous mutations among 104 cancer tissues (2.9%). Then we evaluated these three mutations as well as 8 somatic mutations reported by ICGC or COMP projects. We found that 8 among 11 mutations remarkably inhibited the enzymatic activity of PADI4 protein. To identify novel PADI4 substrates, we conducted proteome analysis using HEK293T cells ectopically transfected with wild type or mutant PADI4 expressing plasmid. Among more than 10000 peptides identified by the liquid chromatography MS/MS analysis, 265 peptides (2.2%) were citrullinated in PADI4-introduced cells, while less than 0.4% of total peptides were citrullinated in control or mock transfected cells. Pathway analysis revealed that RNA binding proteins such as hnRNPs are dominantly citrullinated by PADI4, indicating that possible role of protein citrullination in RNA processing. Citation Format: Chizu Tanikawa, Koji Ueda, Hidewaki Nakagawa, Yusuke Nakamura, Koichi Matsuda. Proteomic analysis of citrullinated targets regulated by the p53-PADI4 pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2014-1562
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corrigendum regulation of histone modification and chromatin structure by the p53 PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
Nature Communications, 2013Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Yusuke Nakamura, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Koichi MatsudaAbstract:Corrigendum: Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
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abstract 5015 regulation of histone modification and chromatin structure by p53 PADI4 pathway
Cancer Research, 2012Co-Authors: Chizu Tanikawa, Yusuke Nakamura, Koichi MatsudaAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Histone proteins are modified in response to various external signals, however their mechanisms are still not fully understood. We here report in vivo and in vitro citrullination of arginine 3 residue of histone H4 (H4R3) in response to DNA damage through the p53-PADI4 pathway. We also observed DNA damage-induced citrullination of lamin C through the p53-PADI4 pathway. Citrullinated H4R3 (cit-H4R3) and citrullinated lamin C are located around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 led to chromatin decondensation and promoted DNA cleavage, while PADI4-/- mice exhibited resistance to radiation-induced apoptosis in the thymus. We also found loss of function mutations of the PADI4 gene in several cancer cell lines. Furthermore, the level of cit-H4R3 was negatively correlated with that of p53 protein in cancer cells and with tumor size in non-small cell lung cancer tissues. Our findings reveal that citrullination of H4R3 would be an “apoptotic histone code” to detect damaged cells and induce nuclear fragmentation, which plays a crucial role in carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5015. doi:1538-7445.AM2012-5015
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regulation of histone modification and chromatin structure by the p53 PADI4 pathway
Nature Communications, 2012Co-Authors: Chizu Tanikawa, Akari Suzuki, Kazuhiko Yamamoto, Koji Ueda, Martha Espinosa, Ken Masuda, Eiju Tsuchiya, Yataro Daigo, Yusuke NakamuraAbstract:PADI4 is an enzyme that converts arginine residues to citrulline. Here, Tanikawa and colleagues show that, in response to DNA damage, histone H4 and Lamin C are citrullinated in a p53 and PADI4-dependent manner and PADI4-dependent manner and PADI4 null mice are resistant to radiation-induced apoptosis in the thymus.
Changwon Kang - One of the best experts on this subject based on the ideXlab platform.
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peptidyl arginine deiminase type iv PADI4 haplotypes interact with shared epitope regardless of anti cyclic citrullinated peptide antibody or erosive joint status in rheumatoid arthritis a case control study
Arthritis Research & Therapy, 2010Co-Authors: Soyoung Bang, Chanbum Choi, Yoonkyoung Sung, Changwon KangAbstract:Introduction Anti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status.
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association of anti cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis
Arthritis & Rheumatism, 2007Co-Authors: Chanbum Choi, Changsoo Paul Kang, Changwon KangAbstract:Objective Anti–cyclic citrullinated peptide (anti-CCP) antibodies are rheumatoid arthritis (RA)–specific serologic markers. RA susceptibility has been associated with HLA–DRB1 shared epitope (SE) alleles and single-nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA. Methods Three nonsynonymous SNPs in PADI4 (PADI4_89, PADI4_90, and PADI4_92) and SE alleles were genotyped, and serum anti-CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically. Results Anti-CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti-CCP–positive patients with RA with a disease duration of ≤34 months (P = 0.041), but not among patients with a longer disease duration or among those who had erosive RA versus nonerosive RA. In contrast, the levels were significantly higher in SE carriers than in noncarriers among patients with RA with a disease duration of ≥141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA. Conclusion The PADI4 RA risk haplotype is associated with increased anti-CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti-CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.
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Association of Anti–Cyclic citrullinated peptide antibody levels with PADI4 haplotypes in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis
Arthritis & Rheumatism, 2007Co-Authors: Chanbum Choi, Changsoo Paul Kang, Changwon KangAbstract:Objective Anti–cyclic citrullinated peptide (anti-CCP) antibodies are rheumatoid arthritis (RA)–specific serologic markers. RA susceptibility has been associated with HLA–DRB1 shared epitope (SE) alleles and single-nucleotide polymorphism (SNP) haplotypes in the peptidyl arginine deiminase 4 gene (PADI4). This study was undertaken to determine whether anti-CCP levels are associated with PADI4 haplotypes and/or SE alleles in Korean patients with RA. Methods Three nonsynonymous SNPs in PADI4 (PADI4_89, PADI4_90, and PADI4_92) and SE alleles were genotyped, and serum anti-CCP levels were measured, in 311 patients with nonerosive or erosive RA. The relationships between anti-CCP levels and PADI4 haplotypes and/or SE alleles were analyzed statistically. Results Anti-CCP levels were significantly higher in patients carrying the PADI4 RA risk haplotype than in patients who did not have the risk haplotype, among anti-CCP–positive patients with RA with a disease duration of ≤34 months (P = 0.041), but not among patients with a longer disease duration or among those who had erosive RA versus nonerosive RA. In contrast, the levels were significantly higher in SE carriers than in noncarriers among patients with RA with a disease duration of ≥141 months (P = 0.0037) and among those who had erosive RA (P = 0.000098), but not among patients who had a shorter disease duration or those who had nonerosive RA. Conclusion The PADI4 RA risk haplotype is associated with increased anti-CCP levels in RA patients with disease of short duration, and PADI4 may play a role in early RA. In contrast, SE alleles are associated with increased anti-CCP levels in RA patients with very longstanding disease and in patients with erosive RA, suggesting that SE alleles play a role in very late RA.
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a functional haplotype of the PADI4 gene associated with increased rheumatoid arthritis susceptibility in koreans
Arthritis & Rheumatism, 2006Co-Authors: Changsoo Paul Kang, Hyoungseok Ju, Changwon KangAbstract:Objective Anticitrullinating autoantibodies are specific markers for rheumatoid arthritis (RA). A functional haplotype of 4 exonic single-nucleotide polymorphisms (SNPs) in a citrullinating enzyme, peptidylarginine deiminase 4 (PADI4), was shown to be associated with susceptibility to RA in a Japanese population and was shown to increase the stability of PADI4 messenger RNA. However, the association was not confirmed in 4 subsequent studies involving Caucasian RA patients living in the UK, a French Caucasian population, and a Spanish population. The aim of the current study was to investigate the association of SNPs in the PADI4 gene with RA in a Korean population. Methods Four exonic SNPs of the PADI4 gene (PADI4_89, PADI4_90, PADI4_92, and PADI4_104) were genotyped in 545 unrelated patients with RA and 392 controls, using the MassArray SNP genotyping system. Allelic, genotypic, and haplotypic associations of the SNPs with RA susceptibility were examined using the chi-square test and multivariate logistic regression analyses. Results Increased RA susceptibility was significantly associated with the minor alleles of PADI4_89 (P = 2.3 × 10−5), PADI4_90 (P = 2.3 × 10−5), PADI4_92 (P = 2.1 × 10−5), and PADI4_104 (P = 1.1 × 10−3) and the haplotype carrying the 4 minor alleles (P = 1.0 × 10−4). Genotypes carrying the minor alleles and HLA–DRB1 shared epitope (SE) alleles (P = 9.4 × 10−21) were also associated with increased RA susceptibility. The genotypic associations were sustained among individuals who did not carry any SE alleles, except in the case of PADI4_104. Individuals carrying the risk SNPs and/or SE alleles were more susceptible to RA than were individuals carrying neither risk SNPs nor SE alleles. Conclusion The PADI4 SNPs and haplotypes are associated with RA susceptibility in Koreans. Thus, the association of PADI4 with RA may depend on genetic heterogeneity between Asians and Europeans.
