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Article: ISG15: A double edged sword in cancer.

Desai, Shyamal D

2015 Volume 4, Issue 12, Page(s) e1052935

Abstract: Interferon-Stimulated Gene ... ...

Abstract	Interferon-Stimulated Gene 15
Language	English
Publishing date	2015-06-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2645309-5
ISSN	2162-402X ; 2162-4011
ISSN (online)	2162-402X
ISSN	2162-4011
DOI	10.1080/2162402X.2015.1052935
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Article ; Online: Neuropathological Outcomes of Traumatic Brain Injury and Alcohol Use in Males and Females: Studies Using Pre-Clinical Rodent and Clinical Human Specimens.

Schwartzenburg, Joshua B / Cruise, Shealan C / Reed, Ryan E / Hutchinson, Corrine M / Mirzalieva, Oygul S / Edwards, Kimberly N / Edwards, Scott / Gilpin, Nicholas W / Molina, Patricia E / Desai, Shyamal D

Journal of neurotrauma

2023 Volume 40, Issue 21-22, Page(s) 2410–2426

Abstract: Traumatic brain injury (TBI) and alcohol misuse are inextricably linked and can increase the risk for development of neurodegenerative diseases, particularly in military veterans and contact sport athletes. Proteinopathy (defects in protein degradation) ... ...

Abstract	Traumatic brain injury (TBI) and alcohol misuse are inextricably linked and can increase the risk for development of neurodegenerative diseases, particularly in military veterans and contact sport athletes. Proteinopathy (defects in protein degradation) is considered an underlying factor in neurodegenerative diseases. Whether it contributes to TBI/alcohol-mediated neurodegeneration is unexplored, however. Our recent studies have identified ISGylation, a conjugated form of ISG15 (Interferon-Stimulated Gene 15) and inducer of proteinopathy, as a potential mechanistic link underlying TBI-mediated neurodegeneration and proteinopathy in veterans. In the current study, a rat model of combined TBI and alcohol use was utilized to investigate the same relationship. Here, we report sustained induction of Interferon β (IFNβ), changes in TAR DNA Binding 43 (TDP-43) ISGylation levels, TDP-43 proteinopathy (C-terminal fragmentation [CTF]), and neurodegeneration in the ventral horns of the lumbar spinal cords (LSCs) and/or motor cortices (MCs) of female rats post-TBI in a time-dependent manner. In males, these findings mostly remained non-significant, although moderate alcohol use appears to decrease neurodegeneration in males (but not females) post-TBI. We, however, do not claim that moderate alcohol consumption is beneficial for preventing TBI-mediated neurodegeneration. We have previously demonstrated that ISGylation is increased in the LSCs of veterans with TBI/ALS (amyotrophic lateral sclerosis). Here, we show increased ISGylation of TDP-43 in the LSCs of TBI/ALS-afflicted female veterans compared with male veterans. Knowing that ISGylation induces proteinopathy, we suggest targeting ISGylation may prevent proteinopathy-mediated neurodegeneration post-TBI, particularly in women; however, causal studies are required to confirm this claim.
MeSH term(s)	Humans ; Male ; Female ; Animals ; Rats ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Rodentia/metabolism ; Brain Injuries, Traumatic/metabolism ; DNA-Binding Proteins/genetics ; Chronic Traumatic Encephalopathy ; Alcohol Drinking
Chemical Substances	DNA-Binding Proteins
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	645092-1
ISSN	1557-9042 ; 0897-7151
ISSN (online)	1557-9042
ISSN	0897-7151
DOI	10.1089/neu.2023.0074
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Article ; Online: Free ISG15 triggers an antitumor immune response against breast cancer: a new perspective.

Burks, Julian / Reed, Ryan E / Desai, Shyamal D

Oncotarget

2015 Volume 6, Issue 9, Page(s) 7221–7231

Abstract: Interferon-Stimulated Gene 15 (ISG15), an antagonist of the canonical ubiquitin pathway, is frequently overexpressed in various cancers. In cancer cells, ISG15 is detected as free (intracellular) and conjugated to cellular proteins (ISGylation). Free ... ...

Abstract	Interferon-Stimulated Gene 15 (ISG15), an antagonist of the canonical ubiquitin pathway, is frequently overexpressed in various cancers. In cancer cells, ISG15 is detected as free (intracellular) and conjugated to cellular proteins (ISGylation). Free ISG15 is also secreted into the extracellular milieu. ISGylation has protumor functions and extracellular free ISG15 has immunomodulatory properties in vitro. Therefore, whether ISG15 is a tumor suppressor or tumor promoter in vivo remains controversial. The current study aimed to clarify the role of free ISG15 in tumorigenesis. Breast cancer cells stably expressing control, ISG15, and UbcH8 (ISG15-specific E2 ligase) shRNAs were used to assess the immunoregulatory and antitumor function of free ISG15 in cell culture (in vitro) and in nude mice (in vivo). We show that extracellular free ISG15 suppresses breast tumor growth and increases NK cell infiltration into xenografted breast tumors in nude mice, and intracellular free ISG15 enhances major histocompatibility complex (MHC) class I surface expression in breast cancer cells. We conclude that free ISG15 may have antitumor and immunoregulatory function in vivo. These findings provides the basis for developing strategies to increase systemic levels of free ISG15 to treat cancer patients overexpressing the ISG15 pathway.
MeSH term(s)	Animals ; Breast Neoplasms/immunology ; Breast Neoplasms/therapy ; Carcinogenesis ; Cell Line, Tumor ; Cell Transformation, Neoplastic ; Cytokines/metabolism ; Female ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; Humans ; Immune System ; Killer Cells, Natural/cytology ; Major Histocompatibility Complex ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Proteasome Endopeptidase Complex/chemistry ; RNA, Small Interfering/metabolism ; Recombinant Proteins/chemistry ; Ubiquitin/metabolism ; Ubiquitins/metabolism
Chemical Substances	Cytokines ; RNA, Small Interfering ; Recombinant Proteins ; Ubiquitin ; Ubiquitins ; ISG15 protein, human (60267-61-0) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-)
Language	English
Publishing date	2015-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.3372
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Article ; Online: Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study.

Kim, Catherine D / Reed, Ryan E / Juncker, Meredith A / Fang, Zhide / Desai, Shyamal D

Journal of neuropathology and experimental neurology

2016 Volume 76, Issue 7, Page(s) 578–584

Abstract: Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent ... ...

Abstract	Interferon-stimulated gene 15 (ISG15), an antagonist of the ubiquitin pathway, is elevated in cells and brain tissues obtained from ataxia telangiectasia (A-T) patients. Previous studies reveal that an elevated ISG15 pathway inhibits ubiquitin-dependent protein degradation, leading to activation of basal autophagy as a compensatory mechanism for protein turnover in A-T cells. Also, genotoxic stress (ultraviolet [UV] radiation) deregulates autophagy and induces aberrant degradation of ubiquitylated proteins in A-T cells. In the current study, we show that, as in A-T cells, ISG15 protein expression is elevated in cerebellums and various other tissues obtained from Atm-compromised mice in an Atm-allele-dependent manner (Atm+/+ < Atm+/- < Atm-/-). Notably, in cerebellums, the brain part primarily affected in A-T, levels of ISG15 were significantly greater (3-fold higher) than cerebrums obtained from the same set of mice. Moreover, as in A-T cell culture, UV induces aberrant degradation of ubiquitylated proteins and autophagy in Atm-deficient, but not in Atm-proficient, cerebellar brain slices grown in culture. Thus, the ex vivo organotypic A-T mouse brain culture model mimics that of an A-T human cell culture model and could be useful for studying the role of ISG15-dependent proteinopathy in cerebellar neurodegeneration, a hallmark of A-T in humans.
MeSH term(s)	Animals ; Ataxia Telangiectasia/genetics ; Ataxia Telangiectasia/pathology ; Ataxia Telangiectasia Mutated Proteins/deficiency ; Ataxia Telangiectasia Mutated Proteins/genetics ; Autophagy/genetics ; Autophagy/radiation effects ; Cerebellum/metabolism ; Cerebellum/radiation effects ; Cytokines/metabolism ; Disease Models, Animal ; Gene Expression Regulation/genetics ; Gene Expression Regulation/radiation effects ; Genotype ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins/metabolism ; Mutation/genetics ; Organ Culture Techniques ; Ubiquitination/genetics ; Ubiquitination/radiation effects ; Ubiquitins/metabolism ; Ultraviolet Rays
Chemical Substances	Cytokines ; G1p2 protein, mouse ; Map1lc3b protein, mouse ; Microtubule-Associated Proteins ; Ubiquitins ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2016-07-25
Publishing country	England
Document type	Journal Article
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlx038
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Article ; Online: ISG15 deregulates autophagy in genotoxin-treated ataxia telangiectasia cells.

Desai, Shyamal D / Reed, Ryan E / Babu, Shilka / Lorio, Eric A

The Journal of biological chemistry

2012 Volume 288, Issue 4, Page(s) 2388–2402

Abstract: Ataxia-telangiectasia (A-T) is a cerebellar neurodegenerative disorder; however, the basis for the neurodegeneration in A-T is not well established. Lesions in the ubiquitin and autophagy pathways are speculated to contribute to the neurodegeneration in ... ...

Abstract	Ataxia-telangiectasia (A-T) is a cerebellar neurodegenerative disorder; however, the basis for the neurodegeneration in A-T is not well established. Lesions in the ubiquitin and autophagy pathways are speculated to contribute to the neurodegeneration in other neurological diseases and may have a role in A-T neurodegeneration. Our recent studies revealed that the constitutively elevated ISG15 pathway impairs targeted proteasome-mediated protein degradation in A-T cells. Here, we demonstrate that the basal autophagy pathway is activated in the ubiquitin pathway-compromised A-T cells. We also show that genotoxic stress triggers aberrant degradation of the proteasome and autophagy substrates (autophagic flux) in A-T cells. Inhibition of autophagy at an early stage using 3-methyladenine blocked UV-induced autophagic flux in A-T cells. On the other hand, bafilomycin A1, which inhibits autophagy at a late stage, failed to block UV-induced autophagic flux, suggesting that overinduction of autophagy may underlie aberrant autophagic flux in A-T cells. The ISG15-specific shRNA that restored proteasome function restores autophagic function in A-T cells. These findings suggest that autophagy compensates for the ISG15-dependent ablation of proteasome-mediated protein degradation in A-T cells. Genotoxic stress overactivates this compensatory mechanism, triggering aberrant autophagic flux in A-T cells. Supporting the model, we show that autophagy is activated in the brain tissues of human A-T patients. This highlights a plausible causal contribution of a novel "ISG15 proteinopathy" in A-T neuronal cell death.
MeSH term(s)	Ataxia/metabolism ; Ataxia Telangiectasia/metabolism ; Autophagy/genetics ; Autophagy/physiology ; Brain/metabolism ; Cytokines/genetics ; Cytokines/metabolism ; Humans ; Interferons/metabolism ; Lentivirus/metabolism ; Lysosomes/metabolism ; Microscopy, Fluorescence/methods ; Mutagens/chemistry ; Neurodegenerative Diseases/metabolism ; Proteasome Endopeptidase Complex/metabolism ; RNA, Small Interfering/metabolism ; Ubiquitins/genetics ; Ubiquitins/metabolism ; Ultraviolet Rays
Chemical Substances	Cytokines ; Mutagens ; RNA, Small Interfering ; Ubiquitins ; ISG15 protein, human (60267-61-0) ; Interferons (9008-11-1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2012-12-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.403832
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Article ; Online: Suppression of the macrophage proteasome by ethanol impairs MHC class I antigen processing and presentation.

D'Souza, Alain J / Desai, Shyamal D / Rudner, Xiaowen L / Kelly, Michelle N / Ruan, SanBao / Shellito, Judd E

PloS one

2013 Volume 8, Issue 2, Page(s) e56890

Abstract: Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the ... ...

Abstract	Alcohol binge-drinking (acute ethanol consumption) is immunosuppressive and alters both the innate and adaptive arms of the immune system. Antigen presentation by macrophages (and other antigen presenting cells) represents an important function of the innate immune system that, in part, determines the outcome of the host immune response. Ethanol has been shown to suppress antigen presentation in antigen presenting cells though mechanisms of this impairment are not well understood. The constitutive and immunoproteasomes are important components of the cellular proteolytic machinery responsible for the initial steps critical to the generation of MHC Class I peptides for antigen presentation. In this study, we used an in-vitro cell culture model of acute alcohol exposure to study the effect of ethanol on the proteasome function in RAW 264.7 cells. Additionally, primary murine peritoneal macrophages obtained by peritoneal lavage from C57BL/6 mice were used to confirm our cell culture findings. We demonstrate that ethanol impairs proteasome function in peritoneal macrophages through suppression of chymotrypsin-like (Cht-L) proteasome activity as well as composition of the immunoproteasome subunit LMP7. Using primary murine peritoneal macrophages, we have further demonstrated that, ethanol-induced impairment of the proteasome function suppresses processing of antigenic proteins and peptides by the macrophage and in turn suppresses the presentation of these antigens to cells of adaptive immunity. The results of this study provide an important mechanism to explain the immunosuppressive effects of acute ethanol exposure.
MeSH term(s)	Animals ; Antigen Presentation/drug effects ; CD8-Positive T-Lymphocytes/metabolism ; Cell Line ; Cells, Cultured ; Ethanol/pharmacology ; Histocompatibility Antigens Class I/metabolism ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/metabolism
Chemical Substances	Histocompatibility Antigens Class I ; Ethanol (3K9958V90M) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2013-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0056890
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Article: A Ubiquitin-Proteasome Pathway for the Repair of Topoisomerase I-DNA Covalent Complexes

Lin, Chao-Po / Ban, Yi / Lyu, Yi Lisa / Desai, Shyamal D / Liu, Leroy F

Journal of biological chemistry. 2008 July 25, v. 283, no. 30

2008

Abstract: Reversible topoisomerase I (Top1)-DNA cleavage complexes are the key DNA lesion induced by anticancer camptothecins (e.g. topotecan and irinotecan) as well as structurally perturbed DNAs (e.g. oxidatively damaged DNA, UV-irradiated DNA, alkylated DNA, ... ...

Abstract	Reversible topoisomerase I (Top1)-DNA cleavage complexes are the key DNA lesion induced by anticancer camptothecins (e.g. topotecan and irinotecan) as well as structurally perturbed DNAs (e.g. oxidatively damaged DNA, UV-irradiated DNA, alkylated DNA, uracil-substituted DNA, mismatched DNA, gapped and nicked DNA, and DNA with abasic sites). Top1 cleavage complexes arrest transcription and trigger transcription-dependent degradation of Top1, a phenomenon termed Top1 down-regulation. In the current study, we have investigated the role of Top1 down-regulation in the repair of Top1 cleavage complexes. Using quiescent (serum-starved) human WI-38 cells, camptothecin (CPT) was shown to induce Top1 down-regulation, which paralleled the induction of DNA single-strand breaks (SSBs) (assayed by comet assays) and ATM autophosphorylation (at Ser-1981). Interestingly, Top1 down-regulation, induction of DNA SSBs and ATM autophosphorylation were all abolished by the proteasome inhibitor MG132. Furthermore, studies using immunoprecipitation and dominant-negative ubiquitin mutants have suggested a specific requirement for the assembly of Lys-48-linked polyubiquitin chains for CPT-induced Top1 down-regulation. In contrast to the effect of proteasome inhibition, inactivation of PARP1 was shown to increase the amount of CPT-induced SSBs and the level of ATM autophosphorylation. Together, these results support a model in which Top1 cleavage complexes arrest transcription and activate a ubiquitin-proteasome pathway leading to the degradation of Top1 cleavage complexes. Degradation of Top1 cleavage complexes results in the exposure of Top1-concealed SSBs for repair through a PARP1-dependent process.
Language	English
Dates of publication	2008-0725
Size	p. 21074-21083.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: A ubiquitin-proteasome pathway for the repair of topoisomerase I-DNA covalent complexes.

Lin, Chao-Po / Ban, Yi / Lyu, Yi Lisa / Desai, Shyamal D / Liu, Leroy F

The Journal of biological chemistry

2008 Volume 283, Issue 30, Page(s) 21074–21083

Abstract	Reversible topoisomerase I (Top1)-DNA cleavage complexes are the key DNA lesion induced by anticancer camptothecins (e.g. topotecan and irinotecan) as well as structurally perturbed DNAs (e.g. oxidatively damaged DNA, UV-irradiated DNA, alkylated DNA, uracil-substituted DNA, mismatched DNA, gapped and nicked DNA, and DNA with abasic sites). Top1 cleavage complexes arrest transcription and trigger transcription-dependent degradation of Top1, a phenomenon termed Top1 down-regulation. In the current study, we have investigated the role of Top1 down-regulation in the repair of Top1 cleavage complexes. Using quiescent (serum-starved) human WI-38 cells, camptothecin (CPT) was shown to induce Top1 down-regulation, which paralleled the induction of DNA single-strand breaks (SSBs) (assayed by comet assays) and ATM autophosphorylation (at Ser-1981). Interestingly, Top1 down-regulation, induction of DNA SSBs and ATM autophosphorylation were all abolished by the proteasome inhibitor MG132. Furthermore, studies using immunoprecipitation and dominant-negative ubiquitin mutants have suggested a specific requirement for the assembly of Lys-48-linked polyubiquitin chains for CPT-induced Top1 down-regulation. In contrast to the effect of proteasome inhibition, inactivation of PARP1 was shown to increase the amount of CPT-induced SSBs and the level of ATM autophosphorylation. Together, these results support a model in which Top1 cleavage complexes arrest transcription and activate a ubiquitin-proteasome pathway leading to the degradation of Top1 cleavage complexes. Degradation of Top1 cleavage complexes results in the exposure of Top1-concealed SSBs for repair through a PARP1-dependent process.
MeSH term(s)	Animals ; Cell Line ; Cell Proliferation ; Comet Assay ; DNA Damage ; DNA Repair ; DNA Topoisomerases, Type I/chemistry ; Gene Expression Regulation, Enzymologic ; HeLa Cells ; Humans ; Mice ; Mutation ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Ubiquitin/chemistry ; Ubiquitin/metabolism
Chemical Substances	Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
Language	English
Publishing date	2008-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M803493200
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Article ; Online: A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway.

Wood, Laurence M / Sankar, Surendran / Reed, Ryan E / Haas, Arthur L / Liu, Leroy F / McKinnon, Peter / Desai, Shyamal D

PloS one

2011 Volume 6, Issue 1, Page(s) e16422

Abstract: Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA ... ...

Abstract	Ataxia Telangiectasia (A-T) is an inherited immunodeficiency disorder wherein mutation of the ATM kinase is responsible for the A-T pathogenesis. Although the precise role of ATM in A-T pathogenesis is still unclear, its function in responding to DNA damage has been well established. Here we demonstrate that in addition to its role in DNA repair, ATM also regulates proteasome-mediated protein turnover through suppression of the ISG15 pathway. This conclusion is based on three major pieces of evidence: First, we demonstrate that proteasome-mediated protein degradation is impaired in A-T cells. Second, we show that the reduced protein turnover is causally linked to the elevated expression of the ubiquitin-like protein ISG15 in A-T cells. Third, we show that expression of the ISG15 is elevated in A-T cells derived from various A-T patients, as well as in brain tissues derived from the ATM knockout mice and A-T patients, suggesting that ATM negatively regulates the ISG15 pathway. Our current findings suggest for the first time that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which could contribute to progressive neurodegeneration in A-T patients.
MeSH term(s)	Animals ; Ataxia Telangiectasia/metabolism ; Ataxia Telangiectasia/pathology ; Ataxia Telangiectasia Mutated Proteins ; Brain/metabolism ; Cell Cycle Proteins/physiology ; Cells, Cultured ; Cytokines/analysis ; DNA-Binding Proteins/physiology ; Humans ; Mice ; Mice, Knockout ; Proteasome Endopeptidase Complex/metabolism ; Protein-Serine-Threonine Kinases/physiology ; Proteins/metabolism ; Tumor Suppressor Proteins/physiology ; Ubiquitins/analysis ; Up-Regulation
Chemical Substances	Cell Cycle Proteins ; Cytokines ; DNA-Binding Proteins ; G1p2 protein, mouse ; Proteins ; Tumor Suppressor Proteins ; Ubiquitins ; ISG15 protein, human (60267-61-0) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; Atm protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2011-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0016422
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Article: ISG15 as a novel tumor biomarker for drug sensitivity.

Desai, Shyamal D / Wood, Laurence M / Tsai, Yu-Chen / Hsieh, Tao-Shih / Marks, Jeffrey R / Scott, Georgia L / Giovanella, Beppino C / Liu, Leroy F

Molecular cancer therapeutics

2008 Volume 7, Issue 6, Page(s) 1430–1439

Abstract: Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/resistance are largely unknown. Recent studies have shown that the ubiquitin-like ... ...

Abstract	Tumor cells are known to exhibit highly varied sensitivity to camptothecins (CPT; e.g., irinotecan and topotecan). However, the factors that determine CPT sensitivity/resistance are largely unknown. Recent studies have shown that the ubiquitin-like protein, IFN-stimulated gene 15 (ISG15), which is highly elevated in many human cancers and tumor cell lines, antagonizes the ubiquitin/proteasome pathway. In the present study, we show that ISG15 is a determinant for CPT sensitivity/resistance possibly through its effect on proteasome-mediated repair of topoisomerase I (TOP1)-DNA covalent complexes. First, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 (major E2 for ISG15) in breast cancer ZR-75-1 cells decreased CPT sensitivity, suggesting that ISG15 overexpression in tumors could be a factor affecting intrinsic CPT sensitivity in tumor cells. Second, the level of ISG15 was found to be significantly reduced in several tumor cells selected for resistance to CPT, suggesting that altered ISG15 regulation could be a significant determinant for acquired CPT resistance. Parallel to reduced CPT sensitivity, short hairpin RNA-mediated knockdown of either ISG15 or UbcH8 in ZR-75-1 cells resulted in increased proteasomal degradation of CPT-induced TOP1-DNA covalent complexes. Taken together, these results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker for CPT sensitivity.
MeSH term(s)	Biomarkers, Tumor/metabolism ; Breast Neoplasms/enzymology ; Breast Neoplasms/pathology ; Camptothecin/pharmacology ; Cell Line, Tumor ; Cytokines/metabolism ; DNA Topoisomerases, Type I/genetics ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm/drug effects ; Humans ; RNA, Small Interfering/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitins/metabolism
Chemical Substances	Biomarkers, Tumor ; Cytokines ; RNA, Small Interfering ; Ubiquitins ; ISG15 protein, human (60267-61-0) ; UBE2L6 protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2008-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-07-2345
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