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Article ; Online: Direct cellular targets and anticancer mechanisms of the natural product oridonin

Jialin Yao / Lu Liu / Qingxiang Sun / Xiaofei Shen

MedComm – Future Medicine, Vol 2, Iss 1, Pp n/a-n/a (2023)

2023

Abstract: Abstract Cancer is one of the leading causes of death worldwide. The proliferation, survival, and metastasis of cancer cells are governed by a complex series of intracellular and extracellular signaling pathways. Therefore, efficient cancer therapy often ...

Abstract	Abstract Cancer is one of the leading causes of death worldwide. The proliferation, survival, and metastasis of cancer cells are governed by a complex series of intracellular and extracellular signaling pathways. Therefore, efficient cancer therapy often requires the modulation of multiple targets. Besides, the modulation of several biological targets with a single drug can lead to synergistic therapeutic effects and avoid side effects associated with combination therapy. Oridonin, an ent‐kaurane type diterpenoid isolated from Rabdosia rubescens, has been reported to possess potent anti‐inflammatory, antioxidant, anticancer, and neuroprotective activities. Among its many benefits, the anticancer effects have attracted the most attention because of its effectiveness in many tumor cells and its potential to overcome therapeutic resistance. Recently, several proteins involved in oncogenic signaling, including CRM1, PHGDH, HSP70, AML1‐ETO, and STAT3, were identified as functional targets of oridonin and its analogs. The binding mechanism and the consequence of oridonin binding to these oncogenic proteins are summarized and discussed. These advances suggest that oridonin exhibits broad spectrum anticancer effects by targeting multiple oncogenic proteins mainly via Michael addition between its unsaturated ketone and the cysteines in the target proteins. Therefore, oridonin and its derivatives hold the potential to be developed as multitargeting anticancer drugs.
Keywords	anticancer activity ; covalent ; molecular mechanism ; multitargeting ; oridonin ; Medical technology ; R855-855.5 ; Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	572
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nuclear transport proteins

Yang Yang / Lu Guo / Lin Chen / Bo Gong / Da Jia / Qingxiang Sun

Signal Transduction and Targeted Therapy, Vol 8, Iss 1, Pp 1-

structure, function, and disease relevance

2023 Volume 29

Abstract: Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or ... ...

Abstract	Abstract Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport. Many of these nuclear transport proteins play additional and essential roles in mitosis, biomolecular condensation, and gene transcription. Dysregulation of nuclear transport is linked to major human diseases such as cancer, neurodegenerative diseases, and viral infections. Selinexor (KPT-330), an inhibitor targeting the nuclear export factor XPO1 (also known as CRM1), was approved in 2019 to treat two types of blood cancers, and dozens of clinical trials of are ongoing. This review summarizes approximately three decades of research data in this field but focuses on the structure and function of individual nuclear transport proteins from recent studies, providing a cutting-edge and holistic view on the role of nuclear transport proteins in health and disease. In-depth knowledge of this rapidly evolving field has the potential to bring new insights into fundamental biology, pathogenic mechanisms, and therapeutic approaches.
Keywords	Medicine ; R ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Design and structural characterization of autoinhibition-compromised full-length Ran

Yuping Tan / Yuqing Zhang / Qiao Zhou / Da Jia / Qingxiang Sun

Signal Transduction and Targeted Therapy, Vol 6, Iss 1, Pp 1-

2021 Volume 3

Keywords	Medicine ; R ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-02-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: GEF-independent Ran activation shifts a fraction of the protein to the cytoplasm and promotes cell proliferation

Jinhan Zhou / Yuping Tan / Yuqing Zhang / Aiping Tong / Xiaofei Shen / Xiaodong Sun / Da Jia / Qingxiang Sun

Molecular Biomedicine, Vol 1, Iss 1, Pp 1-

2020 Volume 13

Abstract: Abstract Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other functions in the cytoplasm, as well as in cellular ... ...

Abstract	Abstract Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other functions in the cytoplasm, as well as in cellular transformation when switched on. Unlike other members of the GTPase superfamily, Ran binds more tightly to GDP than to GTP due to the presence of an auto-inhibitory C-terminal tail. Multiple missense mutations in the C-terminus of Ran occur in cancers, but their biological significance remains unclear. Here, the quantitative GDP/GTP binding preference of four engineered mutations with unstable C-termini was analyzed using a devised mant-GDP dissociation assay. The results showed that the impact of different C-terminal mutations depends on multiple factors. Although these mutants were more GTP-loaded in human cells, they were shown to be more cytoplasmic, and to support nuclear transport with minimally or partially reduced efficiency. Further, several Ran cancer mutants were compromised in autoinhibition, slightly more GTP-bound, more cytoplasmic, and enhanced the proliferation of A549 and HeLa cells in vitro. Thus, our work reveals a new route of Ran activation independent of guanine nucleotide exchange factor (GEF), which may account for the hyper-proliferation induced by Ran cancer mutations.
Keywords	Small GTPases ; Nuclear transport ; GTP bias ; Activation ; Cancer mutations ; Medicine ; R
Subject code	570
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Springer
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Distinct RanBP1 nuclear export and cargo dissociation mechanisms between fungi and animals

Yuling Li / Jinhan Zhou / Sui Min / Yang Zhang / Yuqing Zhang / Qiao Zhou / Xiaofei Shen / Da Jia / Junhong Han / Qingxiang Sun

eLife, Vol

2019 Volume 8

Abstract: Ran binding protein 1 (RanBP1) is a cytoplasmic-enriched and nuclear-cytoplasmic shuttling protein, playing important roles in nuclear transport. Much of what we know about RanBP1 is learned from fungi. Intrigued by the long-standing paradox of harboring ...

Abstract	Ran binding protein 1 (RanBP1) is a cytoplasmic-enriched and nuclear-cytoplasmic shuttling protein, playing important roles in nuclear transport. Much of what we know about RanBP1 is learned from fungi. Intrigued by the long-standing paradox of harboring an extra NES in animal RanBP1, we discovered utterly unexpected cargo dissociation and nuclear export mechanisms for animal RanBP1. In contrast to CRM1-RanGTP sequestration mechanism of cargo dissociation in fungi, animal RanBP1 solely sequestered RanGTP from nuclear export complexes. In fungi, RanBP1, CRM1 and RanGTP formed a 1:1:1 nuclear export complex; in contrast, animal RanBP1, CRM1 and RanGTP formed a 1:1:2 nuclear export complex. The key feature for the two mechanistic changes from fungi to animals was the loss of affinity between RanBP1-RanGTP and CRM1, since residues mediating their interaction in fungi were not conserved in animals. The biological significances of these different mechanisms in fungi and animals were also studied.
Keywords	nuclear transport ; RanBP1 ; nuclear export signal ; fungi ; animal ; distinct mechanism ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	630
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B

Na Sang / Xi Zhong / Kun Gou / Huan Liu / Jing Xu / Yang Zhou / Xia Zhou / Yuanzhi Liu / Zhiqian Chen / Yue Zhou / Yan Li / Lei Tao / Na Su / Lingyun Zhou / Jiahao Qiu / Xinyu Yang / Zeping Zuo / Li Fu / Jingyao Zhang /

Dan Li / Cong Li / Qingxiang Sun / Jian Lei / Rui Li / Shengyong Yang / Xiaobo Cen / Yinglan Zhao

MedComm, Vol 4, Iss 3, Pp n/a-n/a (2023)

2023

Abstract: Abstract Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show ... ...

Abstract	Abstract Lysine‐specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell‐derived and patient‐derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage‐inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co‐administration of ZY0511 and DTP3, which specifically enhanced the pro‐apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.
Keywords	drug combination ; GADD45B ; hepatocellular carcinoma ; LSD1 inhibitor ; Medicine ; R
Subject code	616
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structure of TBC1D23 N-terminus reveals a novel role for rhodanese domain.

Dingdong Liu / Fan Yang / Zhe Liu / Jinrui Wang / Wenjie Huang / Wentong Meng / Daniel D Billadeau / Qingxiang Sun / Xianming Mo / Da Jia

PLoS Biology, Vol 18, Iss 5, p e

2020 Volume 3000746

Abstract: Members of the Tre2-Bub2-Cdc16 (TBC) family often function to regulate membrane trafficking and to control signaling transductions pathways. As a member of the TBC family, TBC1D23 is critical for endosome-to-Golgi cargo trafficking by serving as a bridge ...

Abstract	Members of the Tre2-Bub2-Cdc16 (TBC) family often function to regulate membrane trafficking and to control signaling transductions pathways. As a member of the TBC family, TBC1D23 is critical for endosome-to-Golgi cargo trafficking by serving as a bridge between Golgi-bound golgin-97/245 and the WASH/FAM21 complex on endosomal vesicles. However, the exact mechanisms by which TBC1D23 regulates cargo transport are poorly understood. Here, we present the crystal structure of the N-terminus of TBC1D23 (D23N), which consists of both the TBC and rhodanese domains. We show that the rhodanese domain is unlikely to be an active sulfurtransferase or phosphatase, despite containing a putative catalytic site. Instead, it packs against the TBC domain and forms part of the platform to interact with golgin-97/245. Using the zebrafish model, we show that impacting golgin-97/245-binding, but not the putative catalytic site, impairs neuronal growth and brain development. Altogether, our studies provide structural and functional insights into an essential protein that is required for organelle-specific trafficking and brain development.
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mechanism of cargo recognition by retromer-linked SNX-BAR proteins.

Xin Yong / Lin Zhao / Wankun Deng / Hongbin Sun / Xue Zhou / Lejiao Mao / Wenfeng Hu / Xiaofei Shen / Qingxiang Sun / Daniel D Billadeau / Yu Xue / Da Jia

PLoS Biology, Vol 18, Iss 3, p e

2020 Volume 3000631

Abstract: Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize ... ...

Abstract	Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.
Keywords	Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of a α-helical molten globule intermediate and structural characterization of β-cardiotoxin, an all β-sheet protein isolated from the venom of Ophiophagus hannah (king cobra).

Roy, Amrita / Qingxiang, Sun / Alex, Chapeaurouge / Rajagopalan, Nandhakishore / Jobichen, Chacko / Sivaraman, J / Kini, R Manjunatha

Protein science : a publication of the Protein Society

2019 Volume 28, Issue 5, Page(s) 952–963

Abstract: β-Cardiotoxin is a novel member of the snake venom three-finger toxin (3FTX) family. This is the first exogenous protein to antagonize β-adrenergic receptors and thereby causing reduction in heart rates (bradycardia) when administered into animals, ... ...

Abstract	β-Cardiotoxin is a novel member of the snake venom three-finger toxin (3FTX) family. This is the first exogenous protein to antagonize β-adrenergic receptors and thereby causing reduction in heart rates (bradycardia) when administered into animals, unlike the conventional cardiotoxins as reported earlier. 3FTXs are stable all β-sheet peptides with 60-80 amino acid residues. Here, we describe the three-dimensional crystal structure of β-cardiotoxin together with the identification of a molten globule intermediate in the unfolding pathway of this protein. In spite of the overall structural similarity of this protein with conventional cardiotoxins, there are notable differences observed at the loop region and in the charge distribution on the surface, which are known to be critical for cytolytic activity of cardiotoxins. The molten globule intermediate state present in the thermal unfolding pathway of β-cardiotoxin was however not observed during the chemical denaturation of the protein. Interestingly, circular dichroism (CD) and NMR studies revealed the presence of α-helical secondary structure in the molten globule intermediate. These results point to substantial conformational plasticity of β-cardiotoxin, which might aid the protein in responding to the sometimes conflicting demands of structure, stability, and function during its biological lifetime.
MeSH term(s)	Animals ; Cardiotoxins/chemistry ; Circular Dichroism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Ophiophagus hannah/metabolism ; Protein Denaturation ; Protein Folding ; Protein Structure, Secondary ; Snake Venoms/chemistry ; Snake Venoms/metabolism
Chemical Substances	Cardiotoxins ; Snake Venoms
Language	English
Publishing date	2019-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.3605
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Article: Reduced thiamine binding is a novel mechanism for TPK deficiency disorder

Huang, Wenjie / Jiao Qin / Dingdong Liu / Yan Wang / Xiaofei Shen / Na Yang / Hui Zhou / Xiao-Tang Cai / Zhi-Ling Wang / Dan Yu / Rong Luo / Qingxiang Sun / Yong-Mei Xie / Da Jia

Molecular genetics and genomics. 2019 Apr., v. 294, no. 2

2019

Abstract: Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B₁) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, ...

Abstract	Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B₁) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, the molecular mechanism of the disease is not entirely clear. Here we report an individual case of episodic encephalopathy, with familial history carrying a novel homozygous TPK1 mutation (p.L28S). The L28S mutation leads to reduced enzymatic activity, both in vitro and in vivo, without impairing thiamine binding and protein stability. Thiamine supplementation averted encephalopathic episodes and restored the patient’s developmental progression. Biochemical characterization of reported TPK1 missense mutations suggested reduced thiamine binding as a new disease mechanism. Importantly, many disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency.
Keywords	encephalopathy ; enzyme activity ; enzymes ; homozygosity ; metabolism ; missense mutation ; mutants ; patients ; therapeutics ; thiamin
Language	English
Dates of publication	2019-04
Size	p. 409-416.
Publishing place	Springer Berlin Heidelberg
Document type	Article
ISSN	1617-4615
DOI	10.1007/s00438-018-1517-3
Database	NAL-Catalogue (AGRICOLA)

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