Publications by authors named "Matthew L Scott"

9 Publications

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Sinner or Saint?: Nck Adaptor Proteins in Vascular Biology.

Front Cell Dev Biol 2021 26;9:688388. Epub 2021 May 26.

Department of Pathology and Translational Pathobiology, Louisiana State University Health - Shreveport, Shreveport, LA, United States.

The Nck family of modular adaptor proteins, including Nck1 and Nck2, link phosphotyrosine signaling to changes in cytoskeletal dynamics and gene expression that critically modulate cellular phenotype. The Nck SH2 domain interacts with phosphotyrosine at dynamic signaling hubs, such as activated growth factor receptors and sites of cell adhesion. The Nck SH3 domains interact with signaling effectors containing proline-rich regions that mediate their activation by upstream kinases. In vascular biology, Nck1 and Nck2 play redundant roles in vascular development and postnatal angiogenesis. However, recent studies suggest that Nck1 and Nck2 differentially regulate cell phenotype in the adult vasculature. Domain-specific interactions likely mediate these isoform-selective effects, and these isolated domains may serve as therapeutic targets to limit specific protein-protein interactions. In this review, we highlight the function of the Nck adaptor proteins, the known differences in domain-selective interactions, and discuss the role of individual Nck isoforms in vascular remodeling and function.
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http://dx.doi.org/10.3389/fcell.2021.688388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187788PMC
May 2021

Young at heart? Drugs of abuse cause early-onset cardiovascular disease in the young.

Heart 2021 Apr 15;107(8):604-606. Epub 2021 Feb 15.

Departments of Pathology, Cellular Biology and Anatomy, and Molecular and Cellular Physiology, LSU Health Shreveport, Shreveport, Louisiana, USA

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http://dx.doi.org/10.1136/heartjnl-2020-318856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075271PMC
April 2021

Human Papillomavirus 16 E5 Inhibits Interferon Signaling and Supports Episomal Viral Maintenance.

J Virol 2020 01 6;94(2). Epub 2020 Jan 6.

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA

Human papillomaviruses (HPVs) infect keratinocytes of stratified epithelia. Long-term persistence of infection is a critical risk factor for the development of HPV-induced malignancies. Through the actions of its oncogenes, HPV evades host immune responses to facilitate its productive life cycle. In this work, we discovered a previously unknown function of the HPV16 E5 oncoprotein in the suppression of interferon (IFN) responses. This suppression is focused on keratinocyte-specific IFN-κ and is mediated through E5-induced changes in growth factor signaling pathways, as identified through phosphoproteomics analysis. The loss of E5 in keratinocytes maintaining the complete HPV16 genome results in the derepression of transcription and subsequent JAK/STAT-dependent upregulation of several IFN-stimulated genes (ISGs) at both the mRNA and protein levels. We also established a link between the loss of E5 and the subsequent loss of genome maintenance and stability, resulting in increased genome integration. Persistent human papillomavirus infections can cause a variety of significant cancers. The ability of HPV to persist depends on evasion of the host immune system. In this study, we show that the HPV16 E5 protein can suppress an important aspect of the host immune response. In addition, we find that the E5 protein is important for helping the virus avoid integration into the host genome, which is a frequent step along the pathway to cancer development.
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http://dx.doi.org/10.1128/JVI.01582-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955282PMC
January 2020

Suppression of Stromal Interferon Signaling by Human Papillomavirus 16.

J Virol 2019 10 12;93(19). Epub 2019 Sep 12.

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport Louisiana, USA

Human papillomaviruses (HPVs) infect squamous epithelia and cause several important cancers. Immune evasion is critical for viral persistence. Fibroblasts in the stromal microenvironment provide growth signals and cytokines that are required for proper epithelial differentiation, maintenance, and immune responses and are critical in the development of many cancers. In this study, we examined the role of epithelial-stromal interactions in the HPV16 life cycle using organotypic (raft) cultures as a model. Rafts were created using uninfected human foreskin keratinocytes (HFKs) and HFKs containing either wild-type HPV16 or HPV16 with a stop mutation to prevent the expression of the viral oncogene E5. Microarray analysis revealed significant changes in gene expression patterns in the stroma in response to HPV16, some of which were E5 dependent. Interferon (IFN)-stimulated genes (ISGs) and extracellular matrix remodeling genes were suppressed, the most prominent pathways affected. , , and were knocked down in stromal fibroblasts using lentiviral short hairpin RNA (shRNA) transduction. HPV late gene expression and viral copy number in the epithelium were increased when the stromal IFN pathway was disrupted, indicating that the stroma helps control the late phase of the HPV life cycle in the epithelium. Increased late gene expression correlated with increased late keratinocyte differentiation but not decreased IFN signaling in the epithelium. These studies show HPV16 has a paracrine effect on stromal innate immunity, reveal a new role for E5 as a stromal innate immune suppressor, and suggest that stromal IFN signaling may influence keratinocyte differentiation. The persistence of high-risk human papillomavirus (HPV) infections is the key risk factor for developing HPV-associated cancers. The ability of HPV to evade host immunity is a critical component of its ability to persist. The environment surrounding a tumor is increasingly understood to be critical in cancer development, including immune evasion. Our studies show that HPV can suppress the expression of immune-related genes in neighboring fibroblasts in a three-dimensional (3D) model of human epithelium. This finding is significant, because it indicates that HPV can control innate immunity not only in the infected cell but also in the microenvironment. In addition, the ability of HPV to regulate stromal gene expression depends in part on the viral oncogene E5, revealing a new function for this protein as an immune evasion factor.
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http://dx.doi.org/10.1128/JVI.00458-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744227PMC
October 2019

Human papillomavirus type 16 E5-mediated upregulation of Met in human keratinocytes.

Virology 2018 06 31;519:1-11. Epub 2018 Mar 31.

Department of Microbiology and Immunology, Louisiana State University Health Sciences Center - Shreveport, 1501 Kings Highway, Shreveport, LA 71130, United States; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center - Shreveport, 1501 Kings Highway, Shreveport, LA 71130, United States. Electronic address:

Human papillomaviruses (HPVs) cause benign lesions that can lead to malignancy. How cellular changes induced by viral oncogenes contribute to the progeny virion production is not always clear. Stromally-derived growth factors and their receptors are critical for development of malignancy, but their impact on the pre-malignant HPV life cycle is unknown. We show that HPV16 increases levels of Met, a growth factor receptor critical for tumor cell invasion, motility, and cancer metastasis. The viral oncogene E5 is primarily responsible for Met upregulation, with E6 playing a minor role. Met induction by E5 requires the epidermal growth factor receptor, which is also increased by E5 at the mRNA level. E5-induced Met contributes motility of HPV-containing cells. Finally, Met signaling is necessary for viral gene expression, particularly in the differentiation-dependent phase of the viral life cycle. These studies show a new role for E5 in epithelial-stromal interactions, with implications for cancer development.
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http://dx.doi.org/10.1016/j.virol.2018.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971161PMC
June 2018

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation.

J Virol 2018 04 28;92(8). Epub 2018 Mar 28.

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA

Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGFβ) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGFβ-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGFβ to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-κ), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGFβ1. TGFβ-mediated IFN-κ transcription only occurs in cells containing HPV16, and this is due to TGFβ1-mediated reversal of HPV-induced methylation of the IFN-κ promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle. Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGFβ signaling, which inhibits viral gene expression. Here, we show that the TGFβ and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-κ by TGFβ. The ability of TGFβ to induce IFN-κ promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGFβ in infected cells.
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http://dx.doi.org/10.1128/JVI.01714-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874427PMC
April 2018

Regulation of the human papillomavirus type 16 late promoter by transcriptional elongation.

Virology 2017 07 24;507:179-191. Epub 2017 Apr 24.

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA. Electronic address:

Transcripts from the late promoter of human papillomavirus type 16 (HPV16) are upregulated upon host cell differentiation. Differentiation-dependent transcript regulation is thought to sequester viral antigens in the uppermost epithelial layers, facilitating immune evasion. The mechanisms regulating late promoter upregulation during differentiation are poorly characterized. We show that the late promoter is upregulated at the transcriptional level and that the viral enhancer stimulates promoter activity. Using kinase inhibition and chromatin immunoprecipitation analysis, we show evidence for differentiation-dependent enhancement of transcript elongation. Three factors that promote transcript elongation, cyclin dependent kinase 9 (CDK9), CDK8 (a subunit of the Mediator complex), and bromodomain containing protein 4 (Brd4) are recruited to viral genomes upon differentiation, and each plays a role in promoter activity. These results shed light on the transcriptional processes utilized by HPV16 for proper regulation of gene expression during the viral life cycle.
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http://dx.doi.org/10.1016/j.virol.2017.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488730PMC
July 2017

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-β-induced cancer-associated fibroblast differentiation.

Oncotarget 2016 May;7(22):32200-9

Louisiana State University Health Sciences Center, Feist-Weiller Cancer Center, Shreveport, LA, USA.

The tumor microenvironment, primarily composed of myofibroblasts, directly influences the progression of solid tumors. Through secretion of growth factors, extracellular matrix deposition, and contractile mechanotransduction, myofibroblasts, or cancer-associated fibroblasts (CAFs), support angiogenesis and cancer cell invasion and metastasis. The differentiation of fibroblasts to CAFs is primarily induced by TGF-β from cancer cells. To discover agents capable of blocking CAF differentiation, we developed a high content immunofluorescence-based assay to screen repurposed chemical libraries utilizing fibronectin expression as an initial CAF marker. Screening of the Prestwick chemical library and NIH Clinical Collection repurposed drug library, totaling over 1700 compounds, identified cardiac glycosides as particularly potent CAF blocking agents. Cardiac glycosides are traditionally used to regulate intracellular calcium by inhibiting the Na+/K+ ATPase to control cardiac contractility. Herein, we report that multiple cardiac glycoside compounds, including digoxin, are able to inhibit TGF-β-induced fibronectin expression at low nanomolar concentrations without undesirable cell toxicity. We found this inhibition to hold true for multiple fibroblast cell lines. Using real-time qPCR, we determined that digoxin prevented induction of multiple CAF markers. Furthermore, we report that digoxin is able to prevent TGF-β-induced fibroblast contraction of extracellular matrix, a major phenotypic consequence of CAF differentiation. Assessing the mechanism of inhibition, we found digoxin reduced SMAD promoter activity downstream of TGF-β, and we provide data that the effect is through inhibition of its known target, the Na+/K+ ATPase. These findings support a critical role for calcium signaling during CAF differentiation and highlight a novel, repurposable modality for cancer therapy.
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http://dx.doi.org/10.18632/oncotarget.8609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078007PMC
May 2016

Synthesis, structure, and stability of adducts between phosphide and amide anions and the Lewis acids borane, tris(pentafluorophenyl)borane, and tris(pentafluorophenyl)alane.

Inorg Chem 2009 Dec;48(23):11474-82

Wolfson Materials and Catalysis Centre, School of Chemistry, University of East Anglia, Norwich NR4 7TJ, UK.

The phosphinoborane adduct H(3)P x B(C(6)F(5))(3) can be deprotonated using LiN(SiMe(3))(2) to give the phosphidoborate salt Li[H(2)PB(C(6)F(5))(3)], which was converted to the phosphidodiborates Li[H(2)P{B(C(6)F(5))(3)}(2)] and Li[H(2)P{B(C(6)F(5))(3)}{BH(3)}] by treatment with an equivalent of B(C(6)F(5))(3) or Me(2)S.BH(3), respectively. A series of anions of the form [RR'P{M(C(6)F(5))(3)}{BH(3)}](-), where R = R' = Ph or R= (t)Bu, R' = H, and M = B or Al, were prepared (through treatment of salts Li[RR'P(BH(3))] with the corresponding Lewis acid) and characterized using multinuclear NMR, elemental analysis and X-ray crystallography. The solid state structures of [Li(Et(2)O)(x)][Ph(2)P{M(C(6)F(5))(3)}{BH(3)}] exhibit eta(2)-bonding of the BH(3) group to the cationic lithium center. The attempted preparation of an analogous series with amide cores of the form [R(2)N{B(C(6)F(5))(3)}{BH(3)}](-) proved unsuccessful; among the competing reaction pathways hydride abstraction occurred preferentially to yield Li[HB(C(6)F(5))(3)] and dimers or higher oligomers with the composition (R(2)NBH(2))(n).
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http://dx.doi.org/10.1021/ic901799qDOI Listing
December 2009
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