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Article ; Online: Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein.

Liao, Chung-Chi / Wang, Yi-Sen / Pi, Wen-Chieh / Wang, Chun-Hsiung / Wu, Yi-Min / Chen, Wei-Yi / Hsia, Kuo-Chiang

2023 Volume 14, Issue 1, Page(s) 5518

Abstract: The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In ... ...

Abstract	The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBP
MeSH term(s)	Active Transport, Cell Nucleus ; TATA-Box Binding Protein/genetics ; Saccharomyces cerevisiae/genetics ; Cryoelectron Microscopy ; Transcription Factors/genetics ; Receptors, Cytoplasmic and Nuclear/genetics ; beta Karyopherins/genetics
Chemical Substances	TATA-Box Binding Protein ; Transcription Factors ; Receptors, Cytoplasmic and Nuclear ; beta Karyopherins
Language	English
Publishing date	2023-09-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41206-9
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Article ; Online: A PRC2-Kdm5b axis sustains tumorigenicity of acute myeloid leukemia.

Ren, Zhihong / Kim, Arum / Huang, Yu-Ting / Pi, Wen-Chieh / Gong, Weida / Yu, Xufen / Qi, Jun / Jin, Jian / Cai, Ling / Roeder, Robert G / Chen, Wei-Yi / Wang, Gang Greg

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 9

Abstract: Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML ... ...

Abstract	Acute myeloid leukemias (AMLs) with the NUP98-NSD1 or mixed lineage leukemia (MLL) rearrangement (MLL-r) share transcriptomic profiles associated with stemness-related gene signatures and display poor prognosis. The molecular underpinnings of AML aggressiveness and stemness remain far from clear. Studies with EZH2 enzymatic inhibitors show that polycomb repressive complex 2 (PRC2) is crucial for tumorigenicity in NUP98-NSD1
MeSH term(s)	Animals ; Carcinogenesis ; Gene Expression Profiling ; Histone Demethylases/metabolism ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Mice ; Nuclear Proteins/metabolism ; Oncogene Proteins/metabolism ; Polycomb Repressive Complex 2/antagonists & inhibitors ; Polycomb Repressive Complex 2/metabolism ; Protein Binding ; Repressor Proteins/metabolism ; Sequence Analysis, RNA/methods
Chemical Substances	Nuclear Proteins ; Oncogene Proteins ; Repressor Proteins ; Histone Demethylases (EC 1.14.11.-) ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM5B protein, human (EC 1.14.11.-) ; Polycomb Repressive Complex 2 (EC 2.1.1.43)
Language	English
Publishing date	2022-02-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2122940119
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Article ; Online: Karyopherin Kap114p-mediated trans-repression controls ribosomal gene expression under saline stress.

Liao, Chung-Chi / Shankar, Sahana / Pi, Wen-Chieh / Chang, Chih-Chia / Ahmed, Golam Rizvee / Chen, Wei-Yi / Hsia, Kuo-Chiang

EMBO reports

2020 Volume 21, Issue 7, Page(s) e48324

Abstract: Nuclear accessibility of transcription factors controls gene expression, co-regulated by Ran-dependent nuclear localization and a competitive regulatory network. Here, we reveal that nuclear import factor-facilitated transcriptional repression attenuates ...

Abstract	Nuclear accessibility of transcription factors controls gene expression, co-regulated by Ran-dependent nuclear localization and a competitive regulatory network. Here, we reveal that nuclear import factor-facilitated transcriptional repression attenuates ribosome biogenesis under chronic salt stress. Kap114p, one of the karyopherin-βs (Kap-βs) that mediates nuclear import of yeast TATA-binding protein (yTBP), exhibits a yTBP-binding affinity four orders of magnitude greater than its counterparts and suppresses binding of yTBP with DNA. Our crystal structure of Kap114p reveals an extensively negatively charged concave surface, accounting for high-affinity basic-protein binding. KAP114 knockout in yeast leads to a high-salt growth defect, with transcriptomic analyses revealing that Kap114p modulates expression of genes associated with ribosomal biogenesis by suppressing yTBP binding to target promoters, a trans-repression mechanism we attribute to reduced nuclear Ran levels under salinity stress. Our findings reveal that Ran integrates the nuclear transport pathway and transcription regulatory network, allowing yeast to respond to environmental stresses.
MeSH term(s)	Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Gene Expression ; Karyopherins ; Nuclear Proteins/metabolism ; Ribosomes/genetics ; Ribosomes/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; beta Karyopherins/genetics
Chemical Substances	Karyopherins ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; beta Karyopherins
Language	English
Publishing date	2020-06-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.201948324
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Zs.A 5433: 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)
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Article ; Online: EZH2 noncanonically binds cMyc and p300 through a cryptic transactivation domain to mediate gene activation and promote oncogenesis.

Wang, Jun / Yu, Xufen / Gong, Weida / Liu, Xijuan / Park, Kwang-Su / Ma, Anqi / Tsai, Yi-Hsuan / Shen, Yudao / Onikubo, Takashi / Pi, Wen-Chieh / Allison, David F / Liu, Jing / Chen, Wei-Yi / Cai, Ling / Roeder, Robert G / Jin, Jian / Wang, Gang Greg

Nature cell biology

2022 Volume 24, Issue 3, Page(s) 384–399

Abstract: Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and ... ...

Abstract	Canonically, EZH2 serves as the catalytic subunit of PRC2, which mediates H3K27me3 deposition and transcriptional repression. Here, we report that in acute leukaemias, EZH2 has additional noncanonical functions by binding cMyc at non-PRC2 targets and uses a hidden transactivation domain (TAD) for (co)activator recruitment and gene activation. Both canonical (EZH2-PRC2) and noncanonical (EZH2-TAD-cMyc-coactivators) activities of EZH2 promote oncogenesis, which explains the slow and ineffective antitumour effect of inhibitors of the catalytic function of EZH2. To suppress the multifaceted activities of EZH2, we used proteolysis-targeting chimera (PROTAC) to develop a degrader, MS177, which achieved effective, on-target depletion of EZH2 and interacting partners (that is, both canonical EZH2-PRC2 and noncanonical EZH2-cMyc complexes). Compared with inhibitors of the enzymatic function of EZH2, MS177 is fast-acting and more potent in suppressing cancer growth. This study reveals noncanonical oncogenic roles of EZH2, reports a PROTAC for targeting the multifaceted tumorigenic functions of EZH2 and presents an attractive strategy for treating EZH2-dependent cancers.
MeSH term(s)	Carcinogenesis/genetics ; Cytoskeletal Proteins/metabolism ; E1A-Associated p300 Protein ; Enhancer of Zeste Homolog 2 Protein/genetics ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Humans ; Neoplasms ; Proteolysis ; Transcriptional Activation
Chemical Substances	Cytoskeletal Proteins ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; E1A-Associated p300 Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48)
Language	English
Publishing date	2022-02-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-022-00850-x
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Zs.A 5169: 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)
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Article ; Online: Mediator subunit MED1 is required for E2A-PBX1-mediated oncogenic transcription and leukemic cell growth.

Lee, Yu-Ling / Ito, Keiichi / Pi, Wen-Chieh / Lin, I-Hsuan / Chu, Chi-Shuen / Malik, Sohail / Cheng, I-Hsin / Chen, Wei-Yi / Roeder, Robert G

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 6

Abstract: The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for ... ...

Abstract	The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1
MeSH term(s)	B-Lymphocytes/pathology ; Carcinogenesis/genetics ; Carcinogenesis/pathology ; Cell Cycle Checkpoints ; Cell Proliferation/genetics ; Cell Survival ; Core Binding Factor Alpha 2 Subunit/metabolism ; DNA, Neoplasm/metabolism ; Down-Regulation/genetics ; Gene Expression Regulation, Leukemic ; Genes, Neoplasm ; Homeodomain Proteins/metabolism ; Humans ; Leukemia/genetics ; Leukemia/pathology ; Mediator Complex Subunit 1/metabolism ; Oncogene Proteins, Fusion/metabolism ; Protein Binding ; Protein Stability ; Transcription, Genetic
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; DNA, Neoplasm ; Homeodomain Proteins ; Mediator Complex Subunit 1 ; Oncogene Proteins, Fusion ; RUNX1 protein, human ; E2A-Pbx1 fusion protein (146150-85-8)
Language	English
Publishing date	2021-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1922864118
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Article ; Online: E2A-PBX1 functions as a coactivator for RUNX1 in acute lymphoblastic leukemia.

Pi, Wen-Chieh / Wang, Jun / Shimada, Miho / Lin, Jia-Wei / Geng, Huimin / Lee, Yu-Ling / Lu, Rui / Li, Dongxu / Wang, Gang Greg / Roeder, Robert G / Chen, Wei-Yi

Blood

2020 Volume 136, Issue 1, Page(s) 11–23

Abstract: E2A, a basic helix-loop-helix transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B-cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation ... ...

Abstract	E2A, a basic helix-loop-helix transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B-cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation specifically targets the E2A gene and produces an oncogenic E2A-PBX1 fusion protein. Although previous studies have shown the oncogenic functions of E2A-PBX1 in cell and animal models, the E2A-PBX1-enforced cistrome, the E2A-PBX1 interactome, and related mechanisms underlying leukemogenesis remain unclear. Here, by unbiased genomic profiling approaches, we identify the direct target sites of E2A-PBX1 in t(1,19)-positive pre-B ALL cells and show that, compared with normal E2A, E2A-PBX1 preferentially binds to a subset of gene loci cobound by RUNX1 and gene-activating machineries (p300, MED1, and H3K27 acetylation). Using biochemical analyses, we further document a direct interaction of E2A-PBX1, through a region spanning the PBX1 homeodomain, with RUNX1. Our results also show that E2A-PBX1 binding to gene enhancers is dependent on the RUNX1 interaction but not the DNA-binding activity harbored within the PBX1 homeodomain of E2A-PBX1. Transcriptome analyses and cell transformation assays further establish a significant RUNX1 requirement for E2A-PBX1-mediated target gene activation and leukemogenesis. Notably, the RUNX1 locus itself is also directly activated by E2A-PBX1, indicating a multilayered interplay between E2A-PBX1 and RUNX1. Collectively, our study provides the first unbiased profiling of the E2A-PBX1 cistrome in pre-B ALL cells and reveals a previously unappreciated pathway in which E2A-PBX1 acts in concert with RUNX1 to enforce transcriptome alterations for the development of pre-B ALL.
MeSH term(s)	Amino Acid Motifs ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Core Binding Factor Alpha 2 Subunit/chemistry ; Core Binding Factor Alpha 2 Subunit/genetics ; Core Binding Factor Alpha 2 Subunit/physiology ; DNA/metabolism ; Enhancer Elements, Genetic ; Gene Expression Regulation, Leukemic/genetics ; Histone Code ; Homeodomain Proteins/chemistry ; Homeodomain Proteins/physiology ; Humans ; Mediator Complex/metabolism ; Neoplasm Proteins/metabolism ; Oncogene Proteins, Fusion/chemistry ; Oncogene Proteins, Fusion/physiology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Protein Domains ; Protein Interaction Mapping ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; RNA, Neoplasm/biosynthesis ; RNA, Neoplasm/genetics ; Structure-Activity Relationship ; Transcriptome ; p300-CBP Transcription Factors/metabolism
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; Homeodomain Proteins ; Mediator Complex ; Neoplasm Proteins ; Oncogene Proteins, Fusion ; RNA, Messenger ; RNA, Neoplasm ; RUNX1 protein, human ; E2A-Pbx1 fusion protein (146150-85-8) ; DNA (9007-49-2) ; p300-CBP Transcription Factors (EC 2.3.1.48)
Language	English
Publishing date	2020-04-07
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.2019003312
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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)
Zs.MO 364: Show issues

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Article ; Online: Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage.

Shi, Tzu-Hau / Huang, Yi-Long / Chen, Chiao-Che / Pi, Wen-Chieh / Hsu, Yu-Ling / Lo, Lee-Chiang / Chen, Wei-Yi / Fu, Shu-Ling / Lin, Chao-Hsiung

Biochemical and biophysical research communications

2020 Volume 533, Issue 3, Page(s) 467–473

Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by 2019 novel coronavirus (2019-nCoV) has been a crisis of global health, whereas the effective vaccines against 2019-nCoV are still under development. Alternatively, utilization of old drugs or ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic caused by 2019 novel coronavirus (2019-nCoV) has been a crisis of global health, whereas the effective vaccines against 2019-nCoV are still under development. Alternatively, utilization of old drugs or available medicine that can suppress the viral activity or replication may provide an urgent solution to suppress the rapid spread of 2019-nCoV. Andrographolide is a highly abundant natural product of the medicinal plant, Andrographis paniculata, which has been clinically used for inflammatory diseases and anti-viral therapy. We herein demonstrate that both andrographolide and its fluorescent derivative, the nitrobenzoxadiazole-conjugated andrographolide (Andro- NBD), suppressed the main protease (M
MeSH term(s)	Betacoronavirus/enzymology ; Catalytic Domain ; Coronavirus 3C Proteases ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Diterpenes/chemistry ; Diterpenes/pharmacology ; Fluorescent Dyes/chemistry ; Fluorescent Dyes/pharmacology ; Molecular Docking Simulation ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protein Conformation ; Protein Multimerization ; Severe acute respiratory syndrome-related coronavirus/enzymology ; SARS-CoV-2 ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Diterpenes ; Fluorescent Dyes ; Protease Inhibitors ; Viral Nonstructural Proteins ; andrographolide (410105JHGR) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2020.08.086
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Article: Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage

Shi, Tzu-Hau / Huang, Yi-Long / Chen, Chiao-Che / Pi, Wen-Chieh / Hsu, Yu-Ling / Lo, Lee-Chiang / Chen, Wei-Yi / Fu, Shu-Ling / Lin, Chao-Hsiung

Biochemical and biophysical research communications. 2020 Dec. 10, v. 533, no. 3

2020

Abstract	The coronavirus disease 2019 (COVID-19) pandemic caused by 2019 novel coronavirus (2019-nCoV) has been a crisis of global health, whereas the effective vaccines against 2019-nCoV are still under development. Alternatively, utilization of old drugs or available medicine that can suppress the viral activity or replication may provide an urgent solution to suppress the rapid spread of 2019-nCoV. Andrographolide is a highly abundant natural product of the medicinal plant, Andrographis paniculata, which has been clinically used for inflammatory diseases and anti-viral therapy. We herein demonstrate that both andrographolide and its fluorescent derivative, the nitrobenzoxadiazole-conjugated andrographolide (Andro- NBD), suppressed the main protease (Mᵖʳᵒ) activities of 2019-nCoV and severe acute respiratory syndrome coronavirus (SARS-CoV). Moreover, Andro-NBD was shown to covalently link its fluorescence to these proteases. Further mass spectrometry (MS) analysis suggests that andrographolide formed a covalent bond with the active site Cys¹⁴⁵ of either 2019-nCoV Mᵖʳᵒ or SARS-CoV Mᵖʳᵒ. Consistently, molecular modeling analysis supported the docking of andrographolide within the catalytic pockets of both viral Mᵖʳᵒs. Considering that andrographolide is used in clinical practice with acceptable safety and its diverse pharmacological activities that could be beneficial for attenuating COVID-19 symptoms, extensive investigation of andrographolide on the suppression of 2019-nCoV as well as its application in COVID-19 therapy is suggested.
Keywords	Andrographis paniculata ; COVID-19 infection ; Severe acute respiratory syndrome coronavirus ; Severe acute respiratory syndrome coronavirus 2 ; active sites ; andrographolide ; chemical bonding ; fluorescence ; mass spectrometry ; medicinal plants ; medicine ; pandemic ; proteinases ; research ; therapeutics
Language	English
Dates of publication	2020-1210
Size	p. 467-473.
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2020.08.086
Database	NAL-Catalogue (AGRICOLA)

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Article: Heterogeneous Nuclear Ribonucleoproteins A1 and A2 Function in Telomerase-Dependent Maintenance of Telomeres.

Wang, Tong-Hong / Chen, Chin-Chuan / Hsiao, Yuan-Chao / Lin, Yu-Han / Pi, Wen-Chieh / Huang, Pei-Rong / Wang, Tzu-Chien V / Chen, Chi-Yuan

Cancers

2019 Volume 11, Issue 3

Abstract: The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 ... ...

Abstract	The A/B subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs A/B), which includes hnRNP A1, A2/B1, and A3, plays an important role in cell proliferation. The simultaneous suppression of hnRNP A1/A2, but not the suppression of hnRNP A1 or A2 alone, has been shown to inhibit cell proliferation and induce apoptosis in cancer cells, but not in mortal normal cells. However, the molecular basis for such a differential inhibition of cell proliferation remains unknown. Here, we show that the simultaneous suppression of hnRNP A1 and hnRNP A2 resulted in dysfunctional telomeres and induced DNA damage responses in cancer cells. The inhibition of apoptosis did not alleviate the inhibition of cell proliferation nor the formation of dysfunctional telomeres in cancer cells depleted of hnRNP A1/A2. Moreover, while proliferation of mortal normal fibroblasts was not sensitive to the depletion of hnRNP A1/A2, the ectopic expression of hTERT in normal fibroblasts rendered these cells sensitive to proliferation inhibition, which was associated with the production of dysfunctional telomeres. Our study demonstrates that hnRNP A1 and A2 function to maintain telomeres in telomerase-expressing cells only, suggesting that the maintenance of functional telomeres in telomerase-expressing cancer cells employs factors that differ from those used in the telomerase-negative normal cells.
Language	English
Publishing date	2019-03-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers11030334
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Article ; Online: Heterogeneous nuclear ribonucleoproteins A1 and A2 modulate expression of Tid1 isoforms and EGFR signaling in non-small cell lung cancer.

Chen, Chi-Yuan / Jan, Chia-Ing / Pi, Wen-Chieh / Wang, Wen-Lung / Yang, Pan-Chyr / Wang, Tong-Hong / Karni, Rotem / Wang, Tzu-Chien V

Oncotarget

2016 Volume 7, Issue 13, Page(s) 16760–16772

Abstract: The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various ... ...

Abstract	The Tid1 protein is a DnaJ co-chaperone that has two alternative splicing isoforms: Tid1 long form (Tid1-L) and Tid1 short form (Tid1-S). Recent studies have shown that Tid1-L functions as a tumor suppressor by decreasing EGFR signaling in various cancers, including head and neck cancer and non-small cell lung cancer (NSCLC). However, the molecular mechanism responsible for regulating the alternative splicing of Tid1 is not yet known. Two splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNP) A1 and A2, participate in alternative splicing and are known to be overexpressed in lung cancers. In this work, we examined if hnRNP A1 and A2 could regulate the alternative splicing of Tid1 to modulate tumorigenesis in NSCLC. We report that RNAi-mediated depletion of both hnRNP A1/A2 (but not single depletion of either) increased Tid1-L expression, inhibited cell proliferation and attenuated EGFR signaling. Analyses of the expression levels of hnRNP A1, hnRNP A2, EGFR and Tid1-L in NSCLC tissues revealed that hnRNP A1 and A2 are positively correlated with EGFR, but negatively correlated with Tid1-L. NSCLC patients with high-level expression of hnRNP A1, hnRNP A2 and EGFR combined with low-level expression of Tid1-L were associated with poor overall survival. Taken together, our results suggest that hnRNP A1 or A2 are both capable of facilitating the alternative splicing of exon 11 in the Tid1 pre-mRNA, thereby suppressing the expression of Tid1-L and allowing EGFR-related signaling to facilitate NSCLC tumorigenesis.
MeSH term(s)	Alternative Splicing ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/mortality ; Carcinoma, Non-Small-Cell Lung/pathology ; ErbB Receptors/metabolism ; Gene Expression Regulation, Neoplastic/physiology ; HSP40 Heat-Shock Proteins/biosynthesis ; Heterogeneous Nuclear Ribonucleoprotein A1/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism ; Humans ; Kaplan-Meier Estimate ; Lung Neoplasms/metabolism ; Lung Neoplasms/mortality ; Lung Neoplasms/pathology ; Protein Isoforms ; Signal Transduction/physiology
Chemical Substances	DNAJA3 protein, human ; HSP40 Heat-Shock Proteins ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B ; Protein Isoforms ; hnRNP A2 ; hnRNPA1 protein, human ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2016-02-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.7606
Database	MEDical Literature Analysis and Retrieval System OnLINE

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