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Cornell University
1.
McElwee, John.
Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.
Degree: PhD, Veterinary Medicine, 2014, Cornell University
URL: http://hdl.handle.net/1813/36093
► Breast cancer is the most frequently diagnosed cancer in women, with over 1 million new cases in the world each year. Recently, in addition to…
(more)
▼ Breast cancer is the most frequently diagnosed cancer in women, with over 1 million new cases in the world each year. Recently, in addition to genetic mutations, numerous studies have found that epigenetics plays a direct role in the etiology of breast cancer. The PADIs are a family of epigenetic enzymes that catalyze citrullination, with previous work in our lab showing that PADIs can convert both protein and histone arginine to citrulline, leading to the disruption of protein-protein interactions, as well as direct transcriptional downregulation. Previous research has suggested a potential oncogenic role for PADI2 in breast cancer, though no formal analysis existed. The studies herein investigate the potential role of PADI2 as a novel oncogene and therapeutic target in the treatment of breast cancer in vitro and in vivo. First, using an in vitro model of breast cancer progression (MCF10AT), we show that PADI2 is upregulated upon the malignant transformation of cells, especially in MCF10DCIS cells, which recapitulate the highly invasive comedo-like ductal carcinoma in situ (DCIS) tumors seen in humans. Secondly, using RNA-seq, we show that PADI2 is highly correlated with HER2/ERBB2 overexpression across 57 breast cancer cell lines. We concluded this study by validating the use of our first-generation PADI inhibitor, Cl-amidine, as a therapeutic agent for the treatment of breast cancer both in vitro and in vivo. Following this, we further investigated the functional relationship between PADI2 and HER2 expression. Interestingly, PADI2 appears to function both upstream and downstream of HER2, potentially indicating a role in an oncogenic positivefeedback loop with HER2. Previous evidence from our lab established that PADI2 functions as an ER co-activator via the citrullination of histone H3 arginine 26 (H3R26) at ER-target gene promoters. We show here that PADI2 can bind to the HER2 promoter and downstream ERE; thus, suggesting that the epigenetic regulation of HER2 gene expression by PADI2 occurs via similar mechanisms to ER-target genes. Moreover, we were able to validate our highly potent next-generation PADI inhibitor, BB-Cl-amidine, in the treatment of breast cancer cells in vitro. Lastly, using a mouse model of PADI2 overexpression (MMTV-FLAGPADI2), we found that 20% of mice developed skin lesions after five months. These tumors express high levels of transgenic human PADI2 and display markers of increased inflammation and invasiveness-EMT. Furthermore, a subset of these tumors showed via histopathological analysis to have undergone malignant progression to highly invasive squamous cell carcinomas. Collectively, these studies provide functional and mechanistic evidence establishing PADI2 as a potential novel oncogene and target for cancer therapy.
Advisors/Committee Members: Coonrod, Scott A. (chair), Soloway, Paul (committee member), Schimenti, John C. (committee member), Lin, David M. (committee member).
Subjects/Keywords: Peptidylarginine deiminase; Cl-amidine; PADI2
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APA (6th Edition):
McElwee, J. (2014). Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36093
Chicago Manual of Style (16th Edition):
McElwee, John. “Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.” 2014. Doctoral Dissertation, Cornell University. Accessed March 03, 2021.
http://hdl.handle.net/1813/36093.
MLA Handbook (7th Edition):
McElwee, John. “Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target.” 2014. Web. 03 Mar 2021.
Vancouver:
McElwee J. Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1813/36093.
Council of Science Editors:
McElwee J. Identification Of Peptidylarginine Deiminase-2 (Padi2) As A Potential Oncogene And Therapeutic Target. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36093

Cornell University
2.
Mohanan Nair Padmini, Sunish.
Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.
Degree: PhD, Veterinary Medicine, 2014, Cornell University
URL: http://hdl.handle.net/1813/36176
► Numerous recent studies have shown that epigenetic modifications play a significant role in cancer pathogenesis. The PADs are a family of epigenetic enzymes that catalyze…
(more)
▼ Numerous recent studies have shown that epigenetic modifications play a significant role in cancer pathogenesis. The PADs are a family of epigenetic enzymes that catalyze citrullination, a reaction by which PADs convert peptidyl-arginine to neutral citrulline, leading to the disruption of protein-protein interactions. Our lab has found that PAD2 has a critical role in breast cancer progression. The goal of this thesis research was to further elucidate the role of PAD2 in epithelial carcinogenesis using PAD2 overexpression tumor cell lines and a MMTV-FLAG-hPAD2 transgenic mouse model. We also aimed to evaluate how PAD2 may play a direct role in regulating chronic inflammation via macrophage extracellular chromatin trap release ("ETosis"). Interestingly, we found that 40% of the MMTV-FLAG-hPAD2 overexpressing transgenic mice developed proliferative skin lesions after five months of age. The tumors expressed the transgenic form of FLAG-hPAD2 and showed increased expression for inflammatory cytokines such as IL6 and IL8. As the next step we conducted a two-stage chemical carcinogenesis study to further evaluate the predilection of MMTV-FLAG-hPAD2 mice to develop more invasive skin tumors and compare the histopathology of these tumors with the WT tumors. We found that a higher percentage of MMTV-FLAG-hPAD2 mice developed skin papillomas and the transgenic tumors were more invasive. Furthermore, hPAD2 expression levels were highly positively correlated with chemokine levels and negatively correlated with the cell adhesion markers suggesting the role of PAD2 in assisting epithelial-mesenchymal transition. We had previously shown that PAD4 isozyme in neutrophils is involved in chromatin decondensation and extracellular chromatin trap release. In this thesis research we provide evidence on how PAD2 is involved in macrophage extracellular trap (MET) release. Using in vitro macrophage culture models, we found that PAD2 is critical in functional MET release and that METs contain high levels of histone H4 citrulline 3 (H4Cit3) modification. Using human tongue SCC tissue, we show that CD68+ macrophage associated ETs exist in tumor tissue and are highly positive for citrullinated histones. Additionally, we show that PAD2-rich macrophages associated with chronic subclinical inflammation in adipose tissue also release METs suggesting the significant role of PAD2 in chronic inflammation via MET release. Collectively, these studies provide strong experimental evidence establishing PAD2 as a potential oncogene, a therapeutic target for immunomodulation and a regulator of obesity and tumor associated inflammation.
Advisors/Committee Members: Coonrod, Scott A. (chair), August, Avery (committee member), Fischbach, Claudia (committee member), Weiss, Robert S. (committee member).
Subjects/Keywords: Peptidylarginine deiminase 2 (PAD2); Cancer progression; Extracellular chromatin traps (ETosis)
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mohanan Nair Padmini, S. (2014). Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. (Doctoral Dissertation). Cornell University. Retrieved from http://hdl.handle.net/1813/36176
Chicago Manual of Style (16th Edition):
Mohanan Nair Padmini, Sunish. “Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.” 2014. Doctoral Dissertation, Cornell University. Accessed March 03, 2021.
http://hdl.handle.net/1813/36176.
MLA Handbook (7th Edition):
Mohanan Nair Padmini, Sunish. “Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation.” 2014. Web. 03 Mar 2021.
Vancouver:
Mohanan Nair Padmini S. Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. [Internet] [Doctoral dissertation]. Cornell University; 2014. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/1813/36176.
Council of Science Editors:
Mohanan Nair Padmini S. Role Of Peptidylarginine Deiminase 2 (Pad2) In Epithelial Carcinogenesis And Tumor-Associated Inflammation. [Doctoral Dissertation]. Cornell University; 2014. Available from: http://hdl.handle.net/1813/36176
3.
Cau, Laura.
Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis.
Degree: Docteur es, Biologie structurale et fonctionnelle, 2017, Université Toulouse III – Paul Sabatier
URL: http://www.theses.fr/2017TOU30130
► Les peptidyl-arginine désiminases (PADs) catalysent une modification post-traductionnelle, appelée désimination, qui correspond à la transformation des résidus arginine en résidus citrulline. À ce jour, leur…
(more)
▼ Les peptidyl-arginine désiminases (PADs) catalysent une modification post-traductionnelle, appelée désimination, qui correspond à la transformation des résidus arginine en résidus citrulline. À ce jour, leur rôle est encore mal compris, bien qu'elles aient été impliquées dans divers processus physiologiques et pathologiques. Dans l'épiderme et le follicule pileux, trois d'entre elles sont exprimées, les PAD1, 2 et 3. La désimination de la filaggrine (FLG), protéine essentielle de la différenciation épidermique, semble conduire à sa dissociation des filaments de kératines et permettre sa protéolyse totale. Les acides aminés libres ainsi générés sont nécessaires à la fonction de barrière que remplit la couche cornée, couche cellulaire la plus externe de l'épiderme. Dans le follicule pileux, la désimination de la trichohyaline (TCHH), protéine apparentée à la FLG, augmente sa solubilité et permet sa liaison covalente aux kératines par la transglutaminase 3 (TGase 3), ce qui participe à la formation de la tige pilaire. La description du rôle des PADs au cours de la différenciation des kératinocytes est cependant encore incomplète, et leurs implications dans les maladies de peau peu explorée. L'objectif de mon travail de thèse a été de mieux comprendre le rôle des PADs dans le métabolisme de la FLG et, plus généralement, dans l'homéostasie de l'épiderme et du follicule pileux. Tout d'abord, j'ai montré que la désimination de la FLG humaine par la PAD1 et/ou 3 est une étape majeure qui permet de réguler sa dégradation complète en fonction du taux d'humidité extérieure. Pour cela, j'ai utilisé comme modèle expérimental des épidermes reconstruits humains (ERHs). La diminution de l'humidité relative lors de leur production, de 95% à 30-50%, augmente la protéolyse de la FLG et la genèse des acides aminés correspondants. En parallèle, l'expression de la PAD1 et le taux de désimination de la FLG sont fortement accrus alors que ni l'expression ni l'activité des protéases impliquées dans cette protéolyse ne varient. De plus, le traitement d'ERHs pendant 24 heures avec un inhibiteur des PADs, le Cl-amidine, bloque en partie l'effet de la sécheresse sur le métabolisme de la FLG. J'ai ensuite recherché si la désimination joue un rôle plus global au cours de la différenciation des kératinocytes. J'ai traité des ERHs avec différentes concentrations de Cl-amidine pendant 48 heures et analysé l'effet du traitement sur leur morphologie. L'inhibition de la désimination est dose-dépendante et non toxique. À la plus forte concentration, le Cl-amidine entraîne un amincissement de la couche cornée, une augmentation importante du nombre de cellules transitionnelles, et l'accumulation de mitochondries et de vésicules dans le cytoplasme des kératinocytes granuleux. Ceci permet de proposer que la cornification, dernière étape de la différenciation kératinocytaire, est retardée. De plus, la protéine LC3B-II, marqueur des autophagosomes, étant plus fortement détectée dans les ERHs traités, les PAD1 et/ou 3 pourraient être impliquées dans le…
Advisors/Committee Members: Simon, Michel (thesis director), Takahara, Hidenari (thesis director).
Subjects/Keywords: Peptidyl-arginine désiminase; Peau; Cheveu; Filaggrine; Trichohyaline; Différenciation; Peptidylarginine deiminase; Skin; Hair; Filaggrin; Trichohyalin; Differentiation
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Cau, L. (2017). Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis. (Doctoral Dissertation). Université Toulouse III – Paul Sabatier. Retrieved from http://www.theses.fr/2017TOU30130
Chicago Manual of Style (16th Edition):
Cau, Laura. “Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis.” 2017. Doctoral Dissertation, Université Toulouse III – Paul Sabatier. Accessed March 03, 2021.
http://www.theses.fr/2017TOU30130.
MLA Handbook (7th Edition):
Cau, Laura. “Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis.” 2017. Web. 03 Mar 2021.
Vancouver:
Cau L. Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis. [Internet] [Doctoral dissertation]. Université Toulouse III – Paul Sabatier; 2017. [cited 2021 Mar 03].
Available from: http://www.theses.fr/2017TOU30130.
Council of Science Editors:
Cau L. Importance de la désimination dans l'homéostasie de l'épiderme et du follicule pileux : Importance of deimination in epidermis and hair follicle homeostasis. [Doctoral Dissertation]. Université Toulouse III – Paul Sabatier; 2017. Available from: http://www.theses.fr/2017TOU30130

Brno University of Technology
4.
Tučková, Kristýna.
Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells.
Degree: 2019, Brno University of Technology
URL: http://hdl.handle.net/11012/177494
► Neutrophils are major cell type of innate immunity, that can eliminate pathogens by different mechanisms. One of these mechanisms is called NETosis, which leads to…
(more)
▼ Neutrophils are major cell type of innate immunity, that can eliminate pathogens by different mechanisms. One of these mechanisms is called NETosis, which leads to release of decondensed chromatin and citrullinated histone proteins. Citrullination is post-translational modification catalysed by
peptidylarginine deiminase (PAD) and causing transformation of possitively charged arginin to neutral citrullin and can change expression of cytokine genes. Concetrations of pro-inflammatory cytokines (IL-8, TNF, IL-1) were measured after activation of PAD4 and induction of citrullination. Calcium ionophore was used to induce citrullinaton, Cl-amidine and TDFA were used as inhibitors. Production of cytokines was assessed by ELISA on protein level and by qPCR on mRNA level. It was found that induction of citrullination led to increased concentrations of IL-8 and IL-1. Elevated gene expression of IL-8 was confirmed on mRNA level. Both inhibitors were able to decrease level of histone H3 citrullination and IL-8 and IL-1 concentrations. Expression of TNF was not detected on protein and mRNA level.
Advisors/Committee Members: Číž,, Milan (advisor), Dobeš,, Pavel (referee).
Subjects/Keywords: Citrulinace; Histon H3; Neutrofil; Cytokiny; Peptidylarginindeiminasa; Citrullination; Histone H3; Neutrophil; Cytokines; Peptidylarginine deiminase
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Tučková, K. (2019). Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells. (Thesis). Brno University of Technology. Retrieved from http://hdl.handle.net/11012/177494
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Tučková, Kristýna. “Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells.” 2019. Thesis, Brno University of Technology. Accessed March 03, 2021.
http://hdl.handle.net/11012/177494.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Tučková, Kristýna. “Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells.” 2019. Web. 03 Mar 2021.
Vancouver:
Tučková K. Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells. [Internet] [Thesis]. Brno University of Technology; 2019. [cited 2021 Mar 03].
Available from: http://hdl.handle.net/11012/177494.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Tučková K. Vliv citrulinace histonových proteinů na genovou expresi vybraných genů u buněk myeloidní řady: Influence of the citrulination of histon proteins on the expression of selected genes in myeloid cells. [Thesis]. Brno University of Technology; 2019. Available from: http://hdl.handle.net/11012/177494
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
5.
Doret, Patrick Thomas.
The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
.
Degree: 2008, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/8272
► The repressive structure of chromatin is subject to a diverse collection of post-translational histone modifications which control transcription by regulating access to the underlying DNA.…
(more)
▼ The repressive structure of chromatin is
subject to a diverse collection of post-translational histone modifications which control transcription by regulating access to the underlying DNA. Combinations of epigenetic modifications affect gene expression through the ¡¥histone code¡¦ in a synergistic or antagonistic fashion. These modifications are dynamically regulated allowing chromatin to transition between transcriptionally active or silent states. Thus, epigenetic marks arranged on chromatin function as a fundamental regulatory mechanism to control eukaryotic transcription.
Numerous residues located on histones are covalently modified by regulatory enzymes. Specifically, arginine residues located on core histone N-terminal tails may be mono-methylated, asymmetrically or symmetrically di-methylated. These arginine isoforms affect gene expression through two possible consequences: creation of possible binding sites for proteins and disruption of potential hydrogen bonding. Thus, methylated arginine residues function as crucial epigenetic marks.
Throughout this study, the histone modifying enzyme protein arginine
deiminase 4 (PAD4), which catalyzes the deimination or demethylimination of arginine and mono-methyl arginine, was examined. PAD4 dynamically regulates arginine residues by producing citrulline, an unconventional amino acid. Although PAD4 modifies both arginine and mono-methyl arginine, there has been no evidence supporting that PAD4 regulates the di-methyl form. My studies present data indicating PAD4 may catalyze the ¡¥demethylation¡¦ of di-methyl arginine through a novel regulatory mechanism.
Furthermore, two compounds were used to study the repressive effects of histone citrullination on gene expression. The first compound, Cl-amidine, irreversibly inhibits PAD4 activity thus preventing the dynamic regulation of arginine residues. The second compound, resveratrol, increases expression of p53 target genes. MCF-7 cells treated with either compound displayed elevated expression of the TGF-ƒÒ family member NSAID activated gene-1 (NAG-1). Chromatin immunoprecipitation following treatment with resveratrol revealed reduced levels of histone citrullination and increased levels of histone arginine methylation. Together, these studies indicate that PAD4 negatively regulates the transcription of NAG-1 through citrullination of the promoter nucleosomes.
MCF-7 cells treated with either compound showed reduced levels of growth, a possible downstream effect of the up-regulated tumor suppressor NAG-1. Following translation and secretion, this protein has been postulated to function through membrane bound receptors. Immunostaining against NAG-1 showed increased translocation to the cellular membranes after resveratrol treatment, indicating the protein may be inducing apoptosis. Thus, the inhibition of proliferating MCF-7 cells by resveratrol or Cl-amidine may be, in part, due to the increased expression of NAG-1.
Advisors/Committee Members: Yanming Wang, Thesis Advisor/Co-Advisor.
Subjects/Keywords: NSAID Activated Gene-1; Peptidylarginine Deiminase 4; Citrullination
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Doret, P. T. (2008). The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8272
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Doret, Patrick Thomas. “The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
.” 2008. Thesis, Penn State University. Accessed March 03, 2021.
https://submit-etda.libraries.psu.edu/catalog/8272.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Doret, Patrick Thomas. “The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
.” 2008. Web. 03 Mar 2021.
Vancouver:
Doret PT. The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03].
Available from: https://submit-etda.libraries.psu.edu/catalog/8272.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Doret PT. The Enzymatic Properties of Peptidylarginine Deiminase 4 and its Negative Regulatory Effect Upon NSAID Activated Gene-1
. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8272
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
6.
Li, Pingxin.
ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY.
Degree: 2010, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/11096
► Peptidylarginine deiminase 4 is an enzyme capable of converting both histone arginine and monomethyl-arginine residues into citrulline through reactions termed deimination/citrullination or demethylimination to regulate…
(more)
▼ Peptidylarginine deiminase 4 is an enzyme capable of converting both histone arginine and monomethyl-arginine residues into citrulline through reactions termed deimination/citrullination or demethylimination to regulate histone arginine methylation. This histone posttranslational modification has been related to transcriptional regulation. This dissertation first investigated the role of PAD4 and PAD4 catalyzed histone citrullination in the transcriptional repression of p53-target genes, such as p21/CIP1/WAF1. PAD4 is recruited to the p53-target gene promoter in a p53-dependent manner. Paused RNA Pol II and PAD4 are detected at the p21 promoter before UV irradiation, while RNA Pol II activity and PAD4 association at the p21 promoter are dynamically regulated after UV irradiation. We also detected that PAD4 and histone citrullination coordinate with HDAC2 that mediates histone lysine deacetylation in repressing tumor suppressor gene expression. PAD4 and HDAC2 associated with p21 promoter simultaneously, and both dissociated from several p53-target gene promoters after DNA damage. Our data further revealed that PAD4 promoter association and histone citrullination level are dependent on both p53 and HDAC activity, but HDAC2 promoter association and histone Lys acetylation level are only slightly affected by p53 and PAD4 activity. PAD4 inhibitor Cl-amidine and HDAC inhibitor SAHA induced p53-target gene expression and inhibited cancer cell growth additively in a p53-dependent manner. Using knockout PAD4 mice as a genetic model, we found that PAD4 knockout mice cannot form neutrophil extracellular traps, which are highly decondensed chromatin structures that are important in fighting against invading pathogens after stimulated with chemokines and bacteria. These PAD4 knockout mice are more susceptible to bacterial infection due to the lack of NET-mediated anti-bacterial ability, suggesting an essential role of PAD4 and histone citrullination in innate immunity.
Advisors/Committee Members: Yanming Wang, Dissertation Advisor/Co-Advisor, Yanming Wang, Committee Member, David Scott Gilmour, Committee Chair/Co-Chair, Zhi Chun Lai, Committee Member, Joseph C. Reese, Committee Member, Robert Paulson, Committee Member.
Subjects/Keywords: Peptidylarginine Deiminase 4; Histone Citrullination; p53; p21; Histone Deacetylase 2; Neutrophil Extracellular Traps
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Li, P. (2010). ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11096
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Li, Pingxin. “ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY.” 2010. Thesis, Penn State University. Accessed March 03, 2021.
https://submit-etda.libraries.psu.edu/catalog/11096.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Li, Pingxin. “ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY.” 2010. Web. 03 Mar 2021.
Vancouver:
Li P. ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY. [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 03].
Available from: https://submit-etda.libraries.psu.edu/catalog/11096.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Li P. ANALYSIS OF PEPTIDYLARGININE DEIMINASE 4 AND HISTONE CITRULLINATION IN TRANSCRIPTIONAL REGULATION AND INNATE IMMUNITY. [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11096
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Kent State University
7.
Snow, Alan J.
Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice.
Degree: PhD, College of Arts and Sciences / Department of Biological
Sciences, 2008, Kent State University
URL: http://rave.ohiolink.edu/etdc/view?acc_num=kent1208796428
► Proteins in the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (14-3-3) family are involved in the regulation of many intracellular processes. We have examined the interaction of…
(more)
▼ Proteins in the tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein (14-3-3) family are involved in
the regulation of many intracellular processes. We have examined
the interaction of 14-3-3 with
peptidylarginine deiminase, type VI
(PADI6), an abundant protein found in mammalian oocytes, eggs and
early embryos.
Peptidylarginine deiminases catalyze the
posttranslational modification of
peptidylarginine to citrulline.
PADI6 is associated with oocyte cytoplasmic sheets containing
intermediate filaments and it has been shown that PADI6-deficient
mice are infertile due to disruption of development beyond the
two-cell stage. We found that PADI6 undergoes a dramatic
developmental change in phosphorylation during oocyte maturation.
This change in phosphorylation is linked to an interaction of PADI6
with14-3-3 in the mature egg. Recombinant glutathione-s-transferase
(GST) 14-3-3 pull-down experiments and transgenic tandem affinity
purification with liquid chromatography/mass spectrometry
demonstrates a binding interaction between 14-3-3 and PADI6 in
mature eggs, but not in the immature oocytes. 14-3-3 proteins
modulate or complement intracellular events involving
phosphorylation dependent switching or protein modification. These
results indicate that phosphorylation and/or 14-3-3 binding may
serve as a means of intracellular PADI6 regulation.
Advisors/Committee Members: Kline, Douglas (Committee Chair).
Subjects/Keywords: Biology; oocyte; egg; ovum; PADI6; PAD6; 14-3-3; peptidylarginine deiminase; phosphorylation; mouse; oocyte maturation; gamete biology
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APA (6th Edition):
Snow, A. J. (2008). Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice. (Doctoral Dissertation). Kent State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=kent1208796428
Chicago Manual of Style (16th Edition):
Snow, Alan J. “Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice.” 2008. Doctoral Dissertation, Kent State University. Accessed March 03, 2021.
http://rave.ohiolink.edu/etdc/view?acc_num=kent1208796428.
MLA Handbook (7th Edition):
Snow, Alan J. “Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice.” 2008. Web. 03 Mar 2021.
Vancouver:
Snow AJ. Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice. [Internet] [Doctoral dissertation]. Kent State University; 2008. [cited 2021 Mar 03].
Available from: http://rave.ohiolink.edu/etdc/view?acc_num=kent1208796428.
Council of Science Editors:
Snow AJ. Phosphorylation-dependent interaction of tyrosine 3
monooxygenase/tryptophan 5-monooxygenase activation protein (14
3-3) with PADI6 following oocyte maturation in mice. [Doctoral Dissertation]. Kent State University; 2008. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=kent1208796428
8.
Jenkins, Andrew.
Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer.
Degree: MS, Department of Molecular and Cellular Biology, 2015, University of Guelph
URL: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/8793
► The intrinsically-disordered, 18.5-kiloDalton (kDa) isoform of myelin basic protein (MBP) is a peripheral membrane protein that is essential to proper myelin formation in the central…
(more)
▼ The intrinsically-disordered, 18.5-kiloDalton (kDa) isoform of myelin basic protein (MBP) is a peripheral membrane protein that is essential to proper myelin formation in the central nervous system. MBP multifunctionality arises from its high conformational plasticity and its ability to undergo reversible disorder-to-order transitions. One such transition is the disorder-to-α-helical conformational change which is induced upon MBP-membrane binding. We have investigated the disorder-to-α-helical transition of MBP-derived α-peptides as well as of the full-length 18.5-kDa protein. The data suggest that the disorder-to-α-helical transition of MBP follows a three-state model: disordered↔intermediate↔α-helical, with each of the identified equilibrium states likely representing a conformational ensemble. The disordered state is characterized by slight compaction, whereas the intermediate globally more compact. This study suggests that multifunctionality in MBP could arise from differences in the population of energetically distinct ensemble clusters in different conditions and also provides an example of an IDP that undergoes cooperative global conformation change.
Advisors/Committee Members: Harauz, George (advisor).
Subjects/Keywords: ANS; FRET; Myelin Basic Protein; a-helical; a-helix; alpha-helical; Anilinonaphthalene; Bamm; binding-induced folding; Central Nervous System; Circular Dichroism; CNS; Conformational transitions; deconvolution; deconvolve; deimination; demyelinate; demyelination; disorder to a helical; disorder to order; disordered conformation; Fluoescence; Fluorescence Anisotropy; Fluorescence Spectroscopy; Forster Resonance Energy Transfer; Harauz; IAEDANS; IDP; Intrinsically disordered; Intrinsically disordered protein; Jenkins; kilodaltons; long range intramolecular folding; MBP; MBP-UTC1; MBP-UTC8; membrane mimetic solvents; MS; Multiple Sclerosis; mutagenesis; myelin sheath; neurodegeneration; oligodendrocyte; PAD2; peptidylarginine deiminase type 2; post-translational modification; PTM; random coil; recombinant; recombinant MBP; remyelinate; TFE; thermodynamic ensembles; titration curves; trifluoroethanal; Vassall
…peptidylarginine deiminase-2
PCR
polymerase chain reaction
PLP
proteolipid protein
PTM
post… …number of conformers (31, 47-49).
More specifically, the enzyme peptidylarginine… …deiminase type 2 (PAD2) is known to
cause a highly relevant PTM of MBP that is…
Record Details
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Jenkins, A. (2015). Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer. (Masters Thesis). University of Guelph. Retrieved from https://atrium.lib.uoguelph.ca/xmlui/handle/10214/8793
Chicago Manual of Style (16th Edition):
Jenkins, Andrew. “Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer.” 2015. Masters Thesis, University of Guelph. Accessed March 03, 2021.
https://atrium.lib.uoguelph.ca/xmlui/handle/10214/8793.
MLA Handbook (7th Edition):
Jenkins, Andrew. “Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer.” 2015. Web. 03 Mar 2021.
Vancouver:
Jenkins A. Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer. [Internet] [Masters thesis]. University of Guelph; 2015. [cited 2021 Mar 03].
Available from: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/8793.
Council of Science Editors:
Jenkins A. Conformational Transitions of 18.5-kilodaltons Myelin Basic Protein Studied by Fluorescence Spectroscopy and Forster Resonance Energy Transfer. [Masters Thesis]. University of Guelph; 2015. Available from: https://atrium.lib.uoguelph.ca/xmlui/handle/10214/8793
.