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Thompson Lab Publications

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Articles 1 - 18 of 18

Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson Apr 2018

Photochemical Control Of Protein Arginine Deiminase (Pad) Activity, Santanu Mondal, Sangram S. Parelkar, Mitesh Nagar, Paul R. Thompson

Thompson Lab Publications

Protein Arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis and breast cancer. Therefore, the development of PAD-inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD-inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-Amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis-isomer of 1 is 10-fold more potent than its trans-isomer, whereas the trans-isomer of ...


The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson Mar 2018

The Development Of Benzimidazole-Based Clickable Probes For The Efficient Labeling Of Cellular Protein Arginine Deiminases (Pads), Venkatesh V. Nemmara, Venkataraman Subramanian, Aaron Muth, Santanu Mondal, Ari J. Salinger, Aaron J. Maurais, Ronak Tilvawala, Eranthie Weerapana, Paul R. Thompson

Thompson Lab Publications

Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and "clickable" probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced ...


Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky Jun 2017

Diverse Stimuli Engage Different Neutrophil Extracellular Trap Pathways, Elaine F. Kenny, Alf Herzig, Renate Krüger, Aaron Muth, Santanu Mondal, Paul R. Thompson, Volker Brinkmann, Horst Von Bernuth, Arturo Zychlinsky

Thompson Lab Publications

Neutrophils release neutrophil extracellular traps (NETs) which ensnare pathogens and have pathogenic functions in diverse diseases. We examined the NETosis pathways induced by five stimuli; PMA, the calcium ionophore A23187, nigericin, Candida albicans and Group B Streptococcus. We studied NET production in neutrophils from healthy donors with inhibitors of molecules crucial to PMA induced NETs including protein kinase C, calcium, reactive oxygen species, the enzymes myeloperoxidase (MPO) and neutrophil elastase. Additionally, neutrophils from chronic granulomatous disease patients, carrying mutations in the NADPH oxidase complex or a MPO-deficient patient were examined. We show that PMA, C. albicans and GBS use a ...


Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod May 2017

Role Of Peptidylarginine Deiminase 2 (Pad2) In Mammary Carcinoma Cell Migration, Sachi Horibata, Katherine E. Rogers, David Sadegh, Lynne J. Anguish, John L. Mcelwee, Pragya Shah, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: Penetration of the mammary gland basement membrane by cancer cells is a crucial first step in tumor invasion. Using a mouse model of ductal carcinoma in situ, we previously found that inhibition of peptidylarginine deiminase 2 (PAD2, aka PADI2) activity appears to maintain basement membrane integrity in xenograft tumors. The goal of this investigation was to gain insight into the mechanisms by which PAD2 mediates this process.

METHODS: For our study, we modulated PAD2 activity in mammary ductal carcinoma cells by lentiviral shRNA-mediated depletion, lentiviral-mediated PAD2 overexpression, or PAD inhibition and explored the effects of these treatments on changes ...


Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang Dec 2016

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson Mar 2016

Protein Arginine Methylation And Citrullination In Epigenetic Regulation, Jakob Fuhrmann, Paul R. Thompson

Thompson Lab Publications

The post-translational modification of arginine residues represents a key mechanism for the epigenetic control of gene expression. Aberrant levels of histone arginine modifications have been linked to the development of several diseases including cancer. In recent years, great progress has been made in understanding the physiological role of individual arginine modifications and their effects on chromatin function. The present review aims to summarize the structural and functional aspects of histone arginine modifying enzymes and their impact on gene transcription. We will discuss the potential for targeting these proteins with small molecules in a variety of disease states.


Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue Feb 2016

Citrullination-Acetylation Interplay Guides E2f-1 Activity During The Inflammatory Response, Fatemeh Ghari, Anne-Marie Quirke, Shonagh Munro, Joanna Kawalkowska, Sarah Picaud, Joanna Mcgouran, Venkataraman Subramanian, Aaron Muth, Richard Williams, Benedikt Kessler, Paul R. Thompson, Panagis Fillipakopoulos, Stefan Knapp, Patrick J. Venables, Nicholas B. La Thangue

Thompson Lab Publications

Peptidyl arginine deiminase 4 (PAD4) is a nuclear enzyme that converts arginine residues to citrulline. Although increasingly implicated in inflammatory disease and cancer, the mechanism of action of PAD4 and its functionally relevant pathways remains unclear. E2F transcription factors are a family of master regulators that coordinate gene expression during cellular proliferation and diverse cell fates. We show that E2F-1 is citrullinated by PAD4 in inflammatory cells. Citrullination of E2F-1 assists its chromatin association, specifically to cytokine genes in granulocyte cells. Mechanistically, citrullination augments binding of the BET (bromodomain and extra-terminal domain) family bromodomain reader BRD4 (bromodomain-containing protein 4) to ...


Peptidylarginine Deiminase 3 (Pad3) Is Upregulated By Prolactin Stimulation Of Cid-9 Cells And Expressed In The Lactating Mouse Mammary Gland, Guangyuan Li, Isaac N. Hayward, Brittany R. Jenkins, Heather M. Rothfuss, Coleman H. Young, Marja T. Nevalainen, Aaron Muth, Paul R. Thompson, Amy M. Navratil, Brian D. Cherrington Jan 2016

Peptidylarginine Deiminase 3 (Pad3) Is Upregulated By Prolactin Stimulation Of Cid-9 Cells And Expressed In The Lactating Mouse Mammary Gland, Guangyuan Li, Isaac N. Hayward, Brittany R. Jenkins, Heather M. Rothfuss, Coleman H. Young, Marja T. Nevalainen, Aaron Muth, Paul R. Thompson, Amy M. Navratil, Brian D. Cherrington

Thompson Lab Publications

Peptidylarginine deiminases (PADs) post-translationally convert arginine into neutral citrulline residues. Our past work shows that PADs are expressed in the canine and murine mammary glands; however, the mechanisms regulating PAD expression and the function of citrullination in the normal mammary gland are unclear. Therefore, the first objective herein was to investigate regulation of PAD expression in mammary epithelial cells. We first examined PAD levels in CID-9 cells, which were derived from the mammary gland of mid-pregnant mice. PAD3 expression is significantly higher than all other PAD isoforms and mediates protein citrullination in CID-9 cells. We next hypothesized that prolactin regulates ...


Molecular Targeting Of Protein Arginine Deiminases To Suppress Colitis And Prevent Colon Cancer, Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth Nov 2015

Molecular Targeting Of Protein Arginine Deiminases To Suppress Colitis And Prevent Colon Cancer, Erin E. Witalison, Xiangli Cui, Corey P. Causey, Paul R. Thompson, Lorne J. Hofseth

Thompson Lab Publications

Ulcerative colitis (UC) is a chronic disease, in which the lining of the colon becomes inflamed and develops ulcers leading to abdominal pain, diarrhea, and rectal bleeding. The extent of these symptoms depends on disease severity. The protein arginine deiminase (PAD) family of enzymes converts peptidyl-Arginine to peptidyl-Citrulline through citrullination. PADs are dysregulated, with abnormal citrullination in many diseases, including UC and colorectal cancer (CRC). We have developed the small molecule, pan-PAD inhibitor, Chlor-amidine (Cl-amidine), with multiple goals, including treating UC and preventing CRC. Building off our recent results showing that: 1) Cl-amidine suppresses colitis in vivo in a dextran ...


Chemical Biology Of Protein Arginine Modifications In Epigenetic Regulation, Jakob Fuhrmann, Kathleen W. Clancy, Paul R. Thompson Jun 2015

Chemical Biology Of Protein Arginine Modifications In Epigenetic Regulation, Jakob Fuhrmann, Kathleen W. Clancy, Paul R. Thompson

Thompson Lab Publications

Review article on histone citrullination (arginine deimination), histone arginine methylation, and noncanonical histone arginine modifications.


Peptidylarginine Deiminases: Novel Drug Targets For Prevention Of Neuronal Damage Following Hypoxic Ischemic Insult (Hi) In Neonates., Sigrun Lange, Eridan Rocha-Ferreira, Laura Thei, Priyanka Mawjee, Kate Bennett, Paul R. Thompson, Venkataraman Subramanian, Anthony P. Nicholas, Donald Peebles, Mariya Hristova, Gennadij Raivich Aug 2014

Peptidylarginine Deiminases: Novel Drug Targets For Prevention Of Neuronal Damage Following Hypoxic Ischemic Insult (Hi) In Neonates., Sigrun Lange, Eridan Rocha-Ferreira, Laura Thei, Priyanka Mawjee, Kate Bennett, Paul R. Thompson, Venkataraman Subramanian, Anthony P. Nicholas, Donald Peebles, Mariya Hristova, Gennadij Raivich

Thompson Lab Publications

Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated ...


Modulation Of Calcium-Induced Cell Death In Human Neural Stem Cells By The Novel Peptidylarginine Deiminase-Aif Pathway., Kin Pong U, Venkataraman Subramanian, Antony P. Nicholas, Paul R. Thompson, Patrizia Ferretti Jun 2014

Modulation Of Calcium-Induced Cell Death In Human Neural Stem Cells By The Novel Peptidylarginine Deiminase-Aif Pathway., Kin Pong U, Venkataraman Subramanian, Antony P. Nicholas, Paul R. Thompson, Patrizia Ferretti

Thompson Lab Publications

PADs (peptidylarginine deiminases) are calcium-dependent enzymes that change protein-bound arginine to citrulline (citrullination/deimination) affecting protein conformation and function. PAD up-regulation following chick spinal cord injury has been linked to extensive tissue damage and loss of regenerative capability. Having found that human neural stem cells (hNSCs) expressed PAD2 and PAD3, we studied PAD function in these cells and investigated PAD3 as a potential target for neuroprotection by mimicking calcium-induced secondary injury responses. We show that PAD3, rather than PAD2 is a modulator of cell growth/death and that PAD activity is not associated with caspase-3-dependent cell death, but is required ...


The Induction Of Microrna-16 In Colon Cancer Cells By Protein Arginine Deiminase Inhibition Causes A P53-Dependent Cell Cycle Arrest., Xiangli Cui, Erin E. Witalison, Alena P. Chumanevich, Alexander A. Chumanevich, Deepak Poudyal, Venkataraman Subramanian, Aaron J. Schetter, Curtis C. Harris, Paul R. Thompson, Lorne J. Hofseth Jan 2013

The Induction Of Microrna-16 In Colon Cancer Cells By Protein Arginine Deiminase Inhibition Causes A P53-Dependent Cell Cycle Arrest., Xiangli Cui, Erin E. Witalison, Alena P. Chumanevich, Alexander A. Chumanevich, Deepak Poudyal, Venkataraman Subramanian, Aaron J. Schetter, Curtis C. Harris, Paul R. Thompson, Lorne J. Hofseth

Thompson Lab Publications

Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also ...


Activation Of Pad4 In Net Formation, Amanda S. Rohrbach, Daniel J. Slade, Paul R. Thompson, Kerri A. Mowen Nov 2012

Activation Of Pad4 In Net Formation, Amanda S. Rohrbach, Daniel J. Slade, Paul R. Thompson, Kerri A. Mowen

Thompson Lab Publications

Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 is expressed in granulocytes and is essential for the formation of neutrophil extracellular traps (NETs) via PAD4-mediated histone citrullination. Citrullination of histones is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA that is coated with antimicrobial molecules. Numerous stimuli have been reported to lead to PAD4 activation and NET formation. However, how this signaling process proceeds and how PAD4 becomes activated in cells is largely unknown. Herein, we describe the various ...


Identification Of Padi2 As A Potential Breast Cancer Biomarker And Therapeutic Target., John L. Mcelwee, Sunish Mohanan, Obi L. Griffith, Heike C. Breuer, Lynne J. Anguish, Brian D. Cherrington, Ashley M. Palmer, Louise R. Howe, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Joe W. Gray, Scott A. Coonrod Oct 2012

Identification Of Padi2 As A Potential Breast Cancer Biomarker And Therapeutic Target., John L. Mcelwee, Sunish Mohanan, Obi L. Griffith, Heike C. Breuer, Lynne J. Anguish, Brian D. Cherrington, Ashley M. Palmer, Louise R. Howe, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Joe W. Gray, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti-tumor effects.

METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known ...


Potential Role Of Peptidylarginine Deiminase Enzymes And Protein Citrullination In Cancer Pathogenesis., Sunish Mohanan, Brian D. Cherrington, Sachi Horibata, John L. Mcelwee, Paul R. Thompson, Scott A. Coonrod Sep 2012

Potential Role Of Peptidylarginine Deiminase Enzymes And Protein Citrullination In Cancer Pathogenesis., Sunish Mohanan, Brian D. Cherrington, Sachi Horibata, John L. Mcelwee, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

The peptidylarginine deiminases (PADs) are a family of posttranslational modification enzymes that catalyze the conversion of positively charged protein-bound arginine and methylarginine residues to the uncharged, nonstandard amino acid citrulline. This enzymatic activity is referred to as citrullination or, alternatively, deimination. Citrullination can significantly affect biochemical pathways by altering the structure and function of target proteins. Five mammalian PAD family members (PADs 1-4 and 6) have been described and show tissue-specific distribution. Recent reviews on PADs have focused on their role in autoimmune diseases. Here, we will discuss the potential role of PADs in tumor progression and tumor-associated inflammation. In ...


Potential Role For Padi-Mediated Histone Citrullination In Preimplantation Development., Rui Kan, Mei Jin, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Scott A. Coonrod Jun 2012

Potential Role For Padi-Mediated Histone Citrullination In Preimplantation Development., Rui Kan, Mei Jin, Venkataraman Subramanian, Corey P. Causey, Paul R. Thompson, Scott A. Coonrod

Thompson Lab Publications

BACKGROUND: The peptidylarginine deiminases (PADIs) convert positively charged arginine residues to neutrally charged citrulline on protein substrates in a process that is known as citrullination or deimination. Previous reports have documented roles for histone citrullination in chromatin remodeling and gene regulation in several tissue types, however, a potential role for histone citrullination in chromatin-based activities during early embryogenesis has not been investigated.

RESULTS: In the present study, we tested by laser scanning confocal indirect immunofluorescence microscopy whether specific arginine residues on the histone H3 and H4 N-terminal tails (H4R3, H3R2 + 8 + 17, and H3R26) were citrullinated in mouse oocytes and ...


Genome-Wide Analysis Reveals Padi4 Cooperates With Elk-1 To Activate C-Fos Expression In Breast Cancer Cells., Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W Lee Kraus, Scott A. Coonrod Jun 2011

Genome-Wide Analysis Reveals Padi4 Cooperates With Elk-1 To Activate C-Fos Expression In Breast Cancer Cells., Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W Lee Kraus, Scott A. Coonrod

Thompson Lab Publications

Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed ...