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Article ; Online: CD38 as a pan-hematologic target for chimeric antigen receptor T cells.

Glisovic-Aplenc, Tina / Diorio, Caroline / Chukinas, John A / Veliz, Kimberly / Shestova, Olga / Shen, Feng / Nunez-Cruz, Selene / Vincent, Tiffaney L / Miao, Fei / Milone, Michael C / June, Carl H / Teachey, David T / Tasian, Sarah K / Aplenc, Richard / Gill, Saar

Blood advances

2023 Volume 7, Issue 16, Page(s) 4418–4430

Abstract: Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific ... ...

Abstract	Many hematologic malignancies are not curable with chemotherapy and require novel therapeutic approaches. Chimeric antigen receptor (CAR) T-cell therapy is 1 such approach that involves the transfer of T cells engineered to express CARs for a specific cell-surface antigen. CD38 is a validated tumor antigen in multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL) and is also overexpressed in acute myeloid leukemia (AML). Here, we developed human CD38-redirected T cells (CART-38) as a unified approach to treat 3 different hematologic malignancies that occur across the pediatric-to-adult age spectrum. Importantly, CD38 expression on activated T cells did not impair CART-38 cells expansion or in vitro function. In xenografted mice, CART-38 mediated the rejection of AML, T-ALL, and MM cell lines and primary samples and prolonged survival. In a xenograft model of normal human hematopoiesis, CART-38 resulted in the expected reduction of hematopoietic progenitors, which warrants caution and careful monitoring of this potential toxicity when translating this new immunotherapy into the clinic. Deploying CART-38 against multiple CD38-expressing malignancies is significant because it expands the potential for this novel therapy to affect diverse patient populations.
MeSH term(s)	Adult ; Animals ; Child ; Humans ; Mice ; Hematologic Neoplasms/therapy ; Hematologic Neoplasms/metabolism ; Leukemia, Myeloid, Acute/pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; T-Lymphocytes
Chemical Substances	Receptors, Chimeric Antigen ; CD38 protein, human (EC 3.2.2.5)
Language	English
Publishing date	2023-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022007059
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Article ; Online: Longitudinal Large-Scale Semiquantitative Proteomic Data Stability Across Multiple Instrument Platforms.

Lu, Congcong / Glisovic-Aplenc, Tina / Bernt, Kathrin M / Nestler, Kevin / Cesare, Joseph / Cao, Lusha / Lee, Hyoungjoo / Fazelinia, Hossein / Chinwalla, Asif / Xu, Yang / Shestova, Olga / Xing, Yi / Gill, Saar / Li, Mingyao / Garcia, Benjamin / Aplenc, Richard

Journal of proteome research

2021 Volume 20, Issue 11, Page(s) 5203–5211

Abstract: With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of ... ...

Abstract	With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of these data across time and LC-MS platforms is not well characterized. Here, we evaluate the performance of three LC-MS platforms (Orbitrap Elite, Q Exactive HF, and Orbitrap Fusion) in label-free semiquantitative analysis of cell surface proteins over a six-year period. Sucrose gradient ultracentrifugation was used for surfaceome enrichment, following gel separation for in-depth protein identification. With our established workflow, we consistently detected and reproducibly quantified >2300 putative cell surface proteins in a human acute myeloid leukemia (AML) cell line on all three platforms. To our knowledge this is the first study reporting highly reproducible semiquantitative proteomic data collection of biological replicates across multiple years and LC-MS platforms. These data provide experimental justification for semiquantitative proteomic study designs that are executed over multiyear time intervals and on different platforms. Multiyear and multiplatform experimental designs will likely enable larger scale proteomic studies and facilitate longitudinal proteomic studies by investigators lacking access to high throughput MS facilities. Data are available via ProteomeXchange with identifier PXD022721.
MeSH term(s)	Humans ; Mass Spectrometry/methods ; Proteome/analysis ; Proteomics/methods ; Reproducibility of Results ; Workflow
Chemical Substances	Proteome
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00624
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Article: A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

Weiner, Amber K / Radaoui, Alexander B / Tsang, Matthew / Martinez, Daniel / Sidoli, Simone / Conkrite, Karina L / Delaidelli, Alberto / Modi, Apexa / Rokita, Jo Lynne / Patel, Khushbu / Lane, Maria V / Zhang, Bo / Zhong, Chuwei / Ennis, Brian / Miller, Daniel P / Brown, Miguel A / Rathi, Komal S / Raman, Pichai / Pogoriler, Jennifer /

Bhatti, Tricia / Pawel, Bruce / Glisovic-Aplenc, Tina / Teicher, Beverly / Erickson, Stephen W / Earley, Eric J / Bosse, Kristopher R / Sorensen, Poul H / Krytska, Kateryna / Mosse, Yael P / Havenith, Karin E / Zammarchi, Francesca / van Berkel, Patrick H / Smith, Malcolm A / Garcia, Benjamin A / Maris, John M / Diskin, Sharon J

bioRxiv : the preprint server for biology

2024

Abstract: Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor ... ...

Abstract	Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target. Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer
Language	English
Publishing date	2024-01-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.06.570390
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Article: Longitudinal Large-Scale Semiquantitative Proteomic Data Stability Across Multiple Instrument Platforms

Lu, Congcong / Glisovic-Aplenc, Tina / Bernt, Kathrin M. / Nestler, Kevin / Cesare, Joseph / Cao, Lusha / Lee, Hyoungjoo / Fazelinia, Hossein / Chinwalla, Asif / Xu, Yang / Shestova, Olga / Xing, Yi / Gill, Saar / Li, Mingyao / Garcia, Benjamin / Aplenc, Richard

Journal of proteome research. 2021 Oct. 20, v. 20, no. 11

2021

Abstract	With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of these data across time and LC–MS platforms is not well characterized. Here, we evaluate the performance of three LC–MS platforms (Orbitrap Elite, Q Exactive HF, and Orbitrap Fusion) in label-free semiquantitative analysis of cell surface proteins over a six-year period. Sucrose gradient ultracentrifugation was used for surfaceome enrichment, following gel separation for in-depth protein identification. With our established workflow, we consistently detected and reproducibly quantified >2300 putative cell surface proteins in a human acute myeloid leukemia (AML) cell line on all three platforms. To our knowledge this is the first study reporting highly reproducible semiquantitative proteomic data collection of biological replicates across multiple years and LC–MS platforms. These data provide experimental justification for semiquantitative proteomic study designs that are executed over multiyear time intervals and on different platforms. Multiyear and multiplatform experimental designs will likely enable larger scale proteomic studies and facilitate longitudinal proteomic studies by investigators lacking access to high throughput MS facilities. Data are available via ProteomeXchange with identifier PXD022721.
Keywords	cell lines ; data collection ; gels ; humans ; mass spectrometry ; myeloid leukemia ; proteome ; proteomics ; research ; sucrose ; ultracentrifugation
Language	English
Dates of publication	2021-1020
Size	p. 5203-5211.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00624
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Article ; Online: Improved surfaceome coverage with a label-free nonaffinity-purified workflow.

Glisovic-Aplenc, Tina / Gill, Saar / Spruce, Lynn A / Smith, Ian R / Fazelinia, Hossein / Shestova, Olga / Ding, Hua / Tasian, Sarah K / Aplenc, Richard / Seeholzer, Steven H

Proteomics

2017 Volume 17, Issue 7

Abstract: The proteins of the cellular plasma membrane (PM) perform important functions relating to homeostasis and intercellular communication. Due to its overall low cellular abundance, amphipathic character, and low membrane-to-cytoplasm ratio, the PM proteome ... ...

Abstract	The proteins of the cellular plasma membrane (PM) perform important functions relating to homeostasis and intercellular communication. Due to its overall low cellular abundance, amphipathic character, and low membrane-to-cytoplasm ratio, the PM proteome has been challenging to isolate and characterize, and is poorly represented in standard LC-MS/MS analyses. In this study, we employ sucrose gradient ultracentrifugation for the enrichment of the PM proteome, without chemical labeling and affinity purification, together with GeLCMS and use subsequent bioinformatics tools to select proteins associated with the PM/cell surface, herein referred to as the surfaceome. Using this methodology, we identify over 1900 cell surface associated proteins in a human acute myeloid leukemia cell line. These surface proteins comprise almost 50% of all detected cellular proteins, a number that substantially exceeds the depth of coverage in previously published studies describing the leukemia surfaceome.
MeSH term(s)	Cell Line, Tumor ; Cell Membrane/chemistry ; Cell Membrane/metabolism ; Centrifugation, Density Gradient ; Chromatography, Liquid ; Computational Biology/methods ; Humans ; Leukocytes/chemistry ; Leukocytes/metabolism ; Membrane Proteins/isolation & purification ; Sucrose/chemistry ; Tandem Mass Spectrometry ; Ultracentrifugation/methods
Chemical Substances	Membrane Proteins ; Sucrose (57-50-1)
Language	English
Publishing date	2017-03-06
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.201600344
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Zs.A 5386: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.A 1868: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)

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Article: RNA-binding proteins and post-transcriptional gene regulation.

Glisovic, Tina / Bachorik, Jennifer L / Yong, Jeongsik / Dreyfuss, Gideon

FEBS letters

2008 Volume 582, Issue 14, Page(s) 1977–1986

Abstract: RNAs in cells are associated with RNA-binding proteins (RBPs) to form ribonucleoprotein (RNP) complexes. The RBPs influence the structure and interactions of the RNAs and play critical roles in their biogenesis, stability, function, transport and ... ...

Abstract	RNAs in cells are associated with RNA-binding proteins (RBPs) to form ribonucleoprotein (RNP) complexes. The RBPs influence the structure and interactions of the RNAs and play critical roles in their biogenesis, stability, function, transport and cellular localization. Eukaryotic cells encode a large number of RBPs (thousands in vertebrates), each of which has unique RNA-binding activity and protein-protein interaction characteristics. The remarkable diversity of RBPs, which appears to have increased during evolution in parallel to the increase in the number of introns, allows eukaryotic cells to utilize them in an enormous array of combinations giving rise to a unique RNP for each RNA. In this short review, we focus on the RBPs that interact with pre-mRNAs and mRNAs and discuss their roles in the regulation of post-transcriptional gene expression.
MeSH term(s)	Animals ; Gene Expression Regulation ; Humans ; Ribonucleoproteins/metabolism
Chemical Substances	Ribonucleoproteins
Language	English
Publishing date	2008-03-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2008.03.004
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Article ; Online: Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia.

Blood

2018 Volume 131, Issue 9, Page(s) 995–999

Abstract: As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging ... ...

Abstract	As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.
MeSH term(s)	ADP-ribosyl Cyclase 1/antagonists & inhibitors ; ADP-ribosyl Cyclase 1/metabolism ; Adolescent ; Adult ; Animals ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/pharmacology ; Child ; Child, Preschool ; Female ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Male ; Membrane Glycoproteins/antagonists & inhibitors ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Monoclonal ; Membrane Glycoproteins ; Neoplasm Proteins ; daratumumab (4Z63YK6E0E) ; CD38 protein, human (EC 3.2.2.5) ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6)
Language	English
Publishing date	2018-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2017-07-794214
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Structure of a key intermediate of the SMN complex reveals Gemin2's crucial function in snRNP assembly.

Zhang, Rundong / So, Byung Ran / Li, Pilong / Yong, Jeongsik / Glisovic, Tina / Wan, Lili / Dreyfuss, Gideon

Cell

2011 Volume 146, Issue 3, Page(s) 384–395

Abstract: The SMN complex mediates the assembly of heptameric Sm protein rings on small nuclear RNAs (snRNAs), which are essential for snRNP function. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing ... ...

Abstract	The SMN complex mediates the assembly of heptameric Sm protein rings on small nuclear RNAs (snRNAs), which are essential for snRNP function. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5-containing subunits, respectively. The mechanism by which the Sm proteins are gathered while preventing illicit Sm assembly on non-snRNAs is unknown. Here, we describe the 2.5 Å crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN's Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins, and gripping its bottom and top sides and outer perimeter. Gemin2 reaches into the RNA-binding pocket, preventing RNA binding. Interestingly, SMN-Gemin2 interaction is abrogated by a spinal muscular atrophy (SMA)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide insight into SMN complex assembly and specificity, linking snRNP biogenesis and SMA pathogenesis.
MeSH term(s)	Amino Acid Sequence ; Animals ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Molecular Sequence Data ; Muscular Atrophy, Spinal/genetics ; Muscular Atrophy, Spinal/metabolism ; Mutation ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Ribonucleoproteins, Small Nuclear/metabolism ; SMN Complex Proteins/metabolism ; Sequence Alignment
Chemical Substances	GEMIN2 protein, human ; Nerve Tissue Proteins ; RNA-Binding Proteins ; Ribonucleoproteins, Small Nuclear ; SMN Complex Proteins
Language	English
Publishing date	2011-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2011.06.043
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis.

Cai, Qiliang / Guo, Yi / Xiao, Bingyi / Banerjee, Shuvomoy / Saha, Abhik / Lu, Jie / Glisovic, Tina / Robertson, Erle S

publication RETRACTED

PLoS pathogens

2011 Volume 7, Issue 12, Page(s) e1002418

Abstract: The Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential latent antigens for Epstein-Barr virus (EBV)-induced immortalization of primary human B lymphocytes in vitro, has been implicated in regulating cell proliferation and anti-apoptosis via ... ...

Abstract	The Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential latent antigens for Epstein-Barr virus (EBV)-induced immortalization of primary human B lymphocytes in vitro, has been implicated in regulating cell proliferation and anti-apoptosis via interaction with several cellular and viral factors. Gemin3 (also named DDX20 or DP103) is a member of DEAD RNA helicase family which exhibits diverse cellular functions including DNA transcription, recombination and repair, and RNA metabolism. Gemin3 was initially identified as a binding partner to EBNA2 and EBNA3C. However, the mechanism by which EBNA3C regulates Gemin3 function remains unclear. Here, we report that EBNA3C directly interacts with Gemin3 through its C-terminal domains. This interaction results in increased stability of Gemin3 and its accumulation in both B lymphoma cells and EBV transformed lymphoblastoid cell lines (LCLs). Moreover, EBNA3C promotes formation of a complex with p53 and Gemin3 which blocks the DNA-binding affinity of p53. Small hairpin RNA based knockdown of Gemin3 in B lymphoma or LCL cells remarkably attenuates the ability of EBNA3C to inhibit the transcription activity of p53 on its downstream genes p21 and Bax, as well as apoptosis. These findings provide the first evidence that Gemin3 may be a common target of oncogenic viruses for driving cell proliferation and anti-apoptotic activities.
MeSH term(s)	Antigens, Viral/genetics ; Antigens, Viral/metabolism ; Apoptosis/physiology ; B-Lymphocytes/metabolism ; B-Lymphocytes/virology ; Blotting, Western ; Cell Line, Tumor ; DEAD Box Protein 20/genetics ; DEAD Box Protein 20/metabolism ; Epstein-Barr Virus Infections/genetics ; Epstein-Barr Virus Infections/metabolism ; Epstein-Barr Virus Nuclear Antigens ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/genetics ; Gene Knockdown Techniques ; Herpesvirus 4, Human/genetics ; Herpesvirus 4, Human/metabolism ; Humans ; Immunoprecipitation ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Transfection ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Antigens, Viral ; EBNA-3C, epstein-barr virus ; Epstein-Barr Virus Nuclear Antigens ; TP53 protein, human ; Tumor Suppressor Protein p53 ; DEAD Box Protein 20 (EC 3.6.1.-)
Language	English
Publishing date	2011-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Retracted Publication
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1002418
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Article ; Online: Epstein-Barr virus nuclear antigen 3C stabilizes Gemin3 to block p53-mediated apoptosis.

Qiliang Cai / Yi Guo / Bingyi Xiao / Shuvomoy Banerjee / Abhik Saha / Jie Lu / Tina Glisovic / Erle S Robertson

PLoS Pathogens, Vol 7, Iss 12, p e

2011 Volume 1002418

Abstract	The Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential latent antigens for Epstein-Barr virus (EBV)-induced immortalization of primary human B lymphocytes in vitro, has been implicated in regulating cell proliferation and anti-apoptosis via interaction with several cellular and viral factors. Gemin3 (also named DDX20 or DP103) is a member of DEAD RNA helicase family which exhibits diverse cellular functions including DNA transcription, recombination and repair, and RNA metabolism. Gemin3 was initially identified as a binding partner to EBNA2 and EBNA3C. However, the mechanism by which EBNA3C regulates Gemin3 function remains unclear. Here, we report that EBNA3C directly interacts with Gemin3 through its C-terminal domains. This interaction results in increased stability of Gemin3 and its accumulation in both B lymphoma cells and EBV transformed lymphoblastoid cell lines (LCLs). Moreover, EBNA3C promotes formation of a complex with p53 and Gemin3 which blocks the DNA-binding affinity of p53. Small hairpin RNA based knockdown of Gemin3 in B lymphoma or LCL cells remarkably attenuates the ability of EBNA3C to inhibit the transcription activity of p53 on its downstream genes p21 and Bax, as well as apoptosis. These findings provide the first evidence that Gemin3 may be a common target of oncogenic viruses for driving cell proliferation and anti-apoptotic activities.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2011-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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