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Browsing by Author "Liu, Jing-Yuan"
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Item A novel survivin dimerization inhibitor without a labile hydrazone linker induces spontaneous apoptosis and synergizes with docetaxel in prostate cancer cells(Elsevier, 2022) Peery, Robert; Cui, Qingbin; Kyei-Baffour, Kwaku; Josephraj, Sophia; Huang, Caoqinglong; Dong, Zizheng; Dai, Mingji; Zhang, Jian-Ting; Liu, Jing-Yuan; Pharmacology and Toxicology, School of MedicineSurvivin, a member of the inhibitor of apoptosis protein family, exists as a homodimer and is aberrantly upregulated in a wide spectrum of cancers. It was thought to be an ideal target due to its lack of expression in most adult normal tissues and importance in cancer cell survival. However, it has been challenging to target survivin due to its "undruggable" nature. We previously attempted to target its dimerization domain with a hypothesis that inhibiting survivin dimerization would promote its degradation in proteasome, which led to identification of a lead small-molecule inhibitor, LQZ-7F. LQZ-7F consists of a flat tetracyclic aromatic core with labile hydrazone linking a 1,2,5-oxadiazole moiety. In this study, we tested the hypothesis that LQZ-7F could be developed as a prodrug because the labile hydrazone linker could be hydrolyzed, releasing the tetracyclic aromatic core. To this end, we synthesized the tetracyclic aromatic core (LQZ-7F1) using reported procedure and tested LQZ-7F1 for its biological activities. Here we show that LQZ-7F1 has a significantly improved potency with submicromolar IC50's and induces spontaneous apoptosis in prostate cancer cells. It also more effectively inhibits survivin dimerization and induces survivin degradation in a proteasome-dependent manner than LQZ-7F. We also show that the combination of LQZ-7F1 and docetaxel have strong synergism in inhibiting prostate cancer cell survival. Together, we conclude that the hydrazone linker with the oxadiazole tail is dispensable for survivin inhibition and the survivin dimerization inhibitor, LQZ-7F, may be developed as a prodrug for prostate cancer treatment and to overcome docetaxel resistance.Item Analysis of Pseudo-Symmetry in Protein Homo-Oligomers(2018-12) Rajendran, Catherine Jenifer Rajam; Fang, Shiaofen; Liu, Jing-Yuan; Liang, YaoSymmetry plays a significant role in protein structural assembly and function. This is especially true for large homo-oligomeric protein complexes due to stability and finite control of function. But, symmetry in proteins are not perfect due to unknown reasons and leads to pseudosymmetry. This study focuses on symmetry analysis of homo-oligomers, specifically homo-dimers, homo-trimers and homo-tetramers. We defined Off Symmetry (OS) to measure the overall symmetry of the protein and Structural Index (SI) to quantify the structural difference and Assembly Index (AI) to quantify the assembly difference between the subunits. In most of the symmetrical homo-trimer and homo-tetramer proteins, Assembly Index contributes more to Off Symmetry and in the case of homo-dimer, Structural index contributes more than the Assembly Index. The main chain atom Carbon-Alpha (CA) is more symmetrical than the first side chain atom Carbon-Beta (CB), suggesting protein mobility may contribute to the pseudosymmetry. In addition, Pearson coefficient correlation between their Off-Symmetry and their respective atoms B-Factor (temperature factor) are calculated. We found that the individual residues of a protein in all the subunits are correlated to their average B-Factor of these residues. The correlation with BFactor is stronger in Structure Index than Assembly Index. All these results suggest that protein dynamics play an important role and therefore a larger off-symmetry may indicate a more mobile and flexible protein complex.Item Analysis of pseudo-symmetry in protein oligomers and its correlation with protein dynamics(2017) Shankar, Kavya; Liu, Jing-YuanSymmetry is a feature that can be noticed almost anywhere around us. Animals, for example, have bilateral symmetry whereas flowers have a rotational symmetry. Proteins are complex systems that also exhibit this property as a rule but there is a disturbance in it that prevents it from being perfectly symmetrical. Even homo-oligomers that are made of identical subunits are not exempt from this. In this paper, we focused on protein homo-dimers and homo-trimers and we introduced off-symmetry(OS) to quantify how much a protein complex is off from perfect symmetry. Furthermore, we decomposed off-symmetry into two aspects namely structure index (SI) that measures structural difference and assembly index (AI) that measures assembly difference. We found in most cases, the major contributor to OS is SI in dimers and AI in trimers. In addition, we found that the SI and in turn OS contributed by each residue is positively correlated with their B factors, which indicates that protein flexibility and mobility may contribute to the off-symmetry of protein oligomers.Item Corrigendum: eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation(Frontiers Media, 2021-01-07) Tumia, Rima; Wang, Chao J.; Dong, Tianhan; Ma, Shijie; Beebe, Jenny; Chen, Juan; Dong, Zizheng; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of Medicine[This corrects the article DOI: 10.3389/fcell.2020.00753.].Item Determinants of 14-3-3σ dimerization and function in drug and radiation resistance(2013-11) Li, Zhaomin; Peng, Hui; Qin, Li; Qi, Jing; Zuo, Xiaobing; Liu, Jing-Yuan; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, IU School of MedicineMany proteins exist and function as homodimers. Understanding the detailed mechanism driving the homodimerization is important and will impact future studies targeting the “undruggable” oncogenic protein dimers. In this study, we used 14-3-3σ as a model homodimeric protein and performed a systematic investigation of the potential roles of amino acid residues in the interface for homodimerization. Unlike other members of the conserved 14-3-3 protein family, 14-3-3σ prefers to form a homodimer with two subareas in the dimeric interface that has 180° symmetry. We found that both subareas of the dimeric interface are required to maintain full dimerization activity. Although the interfacial hydrophobic core residues Leu12 and Tyr84 play important roles in 14-3-3σ dimerization, the non-core residue Phe25 appears to be more important in controlling 14-3-3σ dimerization activity. Interestingly, a similar non-core residue (Val81) is less important than Phe25 in contributing to 14-3-3σ dimerization. Furthermore, dissociating dimeric 14-3-3σ into monomers by mutating the Leu12, Phe25, or Tyr84 dimerization residue individually diminished the function of 14-3-3σ in resisting drug-induced apoptosis and in arresting cells at G2/M phase in response to DNA-damaging treatment. Thus, dimerization appears to be required for the function of 14-3-3σ.Item Drugging the "undruggable" DNA-binding domain of STAT3(Impact Journals, 2016-10-11) Zhang, Jian-Ting; Liu, Jing-Yuan; Department of Pharmacology and Toxicology, IU School of MedicineItem Drugging the “Undruggable” DNA-binding Domain of STAT3 for Inhibition of Cancer Cell Migration and Invasion(Office of the Vice Chancellor for Research, 2013-04-05) Huang, Wei; Liu, Jing-Yuan; Dong, Zi-Zheng; Wang, Fang; He, Yan-Tao; Hangoc, Giao; Fu, Xin-Yuan; Broxmeyer, Hal; Zhang, Zhong-Yin; Zhang, Jian-TingSignal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors, and its activation is associated with high histological grade and advanced cancer stage. STAT3 has been shown to play important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor cell immune evasion by regulating the expression of multiple downstream target genes. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced tumors with metastatic potential. Previously, we identified a STAT3 inhibitor, inS3-54, by targeting the “undruggable” DNA-binding site of STAT3 using an improved in-silico screening approach. To further develop this inhibitor, we identified 79 analogues of inS3-54 for the structure-activity relationship analysis. Further study of five effective analogues shows that four analogues (#1, 18, 26, and 69) inhibit STAT3-dependent colony formation of hematopoietic progenitor cells, indicating a higher selectivity for STAT3 than their parental compound, inS3-54 and another analogue #74. These compounds also (1) inhibit STAT3-specific DNA binding activity; (2) suppress proliferation of cancer cells that have constitutively activated STAT3; and (3) inhibit migration and invasion of cancer cells. In addition, analogue #26-conjugated Sepharose beads could also pull down STAT3, revealing a possible direct binding between STAT3 and the inhibitor. Taken together, we conclude that it is possible to inhibit STAT3 by targeting its DNA-binding domain for discovery of anticancer therapeutics and for treatment of metastatic cancers.Item eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation(Frontiers, 2020-08-19) Tumia, Rima; Wang, Chao J.; Dong, Tianhan; Ma, Shijie; Beebe, Jenny; Chen, Juan; Dong, Zizheng; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of MedicineTranslation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a upregulation sensitized cellular response to IR while its downregulation caused resistance to IR. eIF3a increases IR-induced DNA damages and decreases non-homologous end joining (NHEJ) activity by suppressing the synthesis of NHEJ repair proteins. Furthermore, analysis of existing patient database shows that eIF3a expression associates with better overall survival of breast, gastric, lung, and ovarian cancer patients. These findings together suggest that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating the synthesis of DNA repair proteins and, thus, eIIF3a likely contributes to the outcome of cancer patients treated with DNA-damaging strategies including IR.Item FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1(National Academy of Sciences, 2016-10-24) Wu, Xi; Dong, Zizheng; Wang, Chao J.; Barlow, Lincoln James; Fako, Valerie; Serrano, Moises A.; Zou, Yue; Liu, Jing-Yuan; Zhang, Jian-Ting; Department of Pharmacology and Toxicology, School of MedicineFatty acid synthase (FASN), the sole cytosolic mammalian enzyme for de novo lipid synthesis, is crucial for cancer cell survival and associates with poor prognosis. FASN overexpression has been found to cause resistance to genotoxic insults. Here we tested the hypothesis that FASN regulates DNA repair to facilitate survival against genotoxic insults and found that FASN suppresses NF-κB but increases specificity protein 1 (SP1) expression. NF-κB and SP1 bind to a composite element in the poly(ADP-ribose) polymerase 1 (PARP-1) promoter in a mutually exclusive manner and regulate PARP-1 expression. Up-regulation of PARP-1 by FASN in turn increases Ku protein recruitment and DNA repair. Furthermore, lipid deprivation suppresses SP1 expression, which is able to be rescued by palmitate supplementation. However, lipid deprivation or palmitate supplementation has no effect on NF-κB expression. Thus, FASN may regulate NF-κB and SP1 expression using different mechanisms. Altogether, we conclude that FASN regulates cellular response against genotoxic insults by up-regulating PARP-1 and DNA repair via NF-κB and SP1.Item Insight into Conformational Change for 14-3-3σ Protein by Molecular Dynamics Simulation(MDPI, 2014-02-18) Hu, Guodong; Li, Haiyan; Liu, Jing-Yuan; Wang, Jihua; Computer and Information Science, School of Science14-3-3σ is a member of a highly conserved family of 14-3-3 proteins that has a double-edged sword role in human cancers. Former reports have indicated that the 14-3-3 protein may be in an open or closed state. In this work, we found that the apo-14-3-3σ is in an open state compared with the phosphopeptide bound 14-3-3σ complex which is in a more closed state based on our 80 ns molecular dynamics (MD) simulations. The interaction between the two monomers of 14-3-3σ in the open state is the same as that in the closed state. In both open and closed states, helices A to D, which are involved in dimerization, are stable. However, large differences are found in helices E and F. The hydrophobic contacts and hydrogen bonds between helices E and G in apo-14-3-3σ are different from those in the bound 14-3-3σ complex. The restrained and the mutated (Arg56 or Arg129 to alanine) MD simulations indicate that the conformation of four residues (Lys49, Arg56, Arg129 and Tyr130) may play an important role to keep the 14-3-3σ protein in an open or closed state. These results would be useful to evaluate the 14-3-3σ protein structure-function relationship.
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