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1.
Yu Ding ;Yongyan Li ;Junyan You ;Li Yang ;Bobei Chen ;Jianxin Lu ;Min-Xin Guan 《遗传学报》2009,36(4):241-250
Mutations in mitochondrial 12S rRNA gene are one of the most important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we report the characterization of one Han Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing loss. This Chinese family carrying the 12S rRNA A1555G mutation exhibited high penetrance and expressivity of heating impairment. In particular, penetrances of hearing loss in this family pedigree were 43.8% and 25%, respectively, when aminoglycoside-induced heating loss was included or excluded. Mutational analysis of entire mitochondrial genomes in this family showed the homoplasmic A1555G mutation and a set of variants belonging to haplogroup Y2. Of these, the A14693G variant occurred at the extremely conserved nucleotide (conventional position 54) of the TψC-loop of tRNA^Clu and was absent in 156 Chinese controls. Nucleotides at position 54 of tRNAs are often modified, thereby contributing to the structural formation and stabilization of functional tRNAs. Thus, the structural alteration of tRNA by the A14693G variant may lead to a failure in tRNA metabolism and impair mitochondrial protein synthesis, thereby worsening mitochondrial dysfunctions altered by the A1555G mutation. Therefore, the tRNA^Glu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated A1555G mutation in this Chinese pedigree. 相似文献
2.
Jesus Davila-Barboza O.Karina Villanueva-Segura Beatriz Lopez-Monroy Gustavo Ponce-Garcia Cristina Bobadilla-Utrera Mayela Montes-Rincon Zinnia J.Molina-Garza Juan I.Arredondo-Jimenez Iram P.Rodriguez-Sanchez Pablo C.Manrique-Saide Adriana E.Flores 《Insect Science》2019,26(5):809-820
Although having five different ways of transmission the vector-borne is the principal way of transmission of Chagas disease, which involves insects of the subfamily Triatominae (Hemiptera: Reduviidae). Nineteen of the 31 species that occur in Mexico are associated with humans, and all are capable of transmitting the disease. Pyrethroids are the insecticides recommended for the control of these vectors in Mexico. We determined the susceptibility to the pyrethroids dcltamethrin and permethrin of peridomestic populations of Triatoma mazzottii Usinger and two populations of Triatoma longipetmis Usinger in comparison with a reference strain for each species. Bioassays were performed for the determination of the LD50 for both field populations and reference strains. A maximum of 27 fold resistance to deltamethrin was observed in T. mazzottii, meanwhile, for permethrin, T. longipennis from Jalisco show the highest value of 3.19 fold. There was significantly increased activity of esterases in field populations in comparison with their corresponding reference strain. The results of the search of kdr mutations related to the resistance to deltamethrin and permethrin in the evaluated species show the presence of mutations in the field populations, as is the case with individuals of T. mazzottii, for which the mutation was found A943V, and for the two populations of T. longipennis included in this study, we report the presence of the kdr mutation K964R. Evaluation of the various mechanisms involved in resistance to pyrethroids in triatomines from Mexico could guide us to the real justification for insecticide resistance monitoring. 相似文献
3.
Structural features and molecular evolution of Bowman-Birk protease inhibitors and their potential application 总被引:3,自引:0,他引:3
The Bowman-Birk inhibitors (BBIs) are well-studied serine protease inhibitors that are abundant in dicotyledonous and monocotyledonous plants. BBIs from dicots usually have a molecular weight of 8k and are double-headed with two reactive sites, whereas those from monocots can be divided into two classes, one approximately 8 kDa in size with one reactive site (another reactive site was lost) and the other approximately 16 kDa in size with two reactive sites. The reactive site is located at unique exposed surfaces formed by a disulfide-linked β-sheet loop that is highly conserved, rigid and mostly composed of nine residues. The structural features and molecular evolution of inhibitors are described, focusing on the conserved disulfide bridges. The sunflower trypsin inhibitor-1 (SFTI-1), with 14 amino acid residues, is a recently discovered bicyclic inhibitor, and is the most small and potent naturally occurring Bowman-Birk inhibitor.Recently, BBIs have become a hot topic because of their potential applications. BBIs are now used for defense against pathogens and insects in transgenic plants, which has advantages over using toxic and polluting insecticides. BBIs could also be applied in the prevention of cancer, Dengue fever, and inflammatory and allergic disorders, because of their inhibitory activity with respect to the serine proteases that play apivotal role in the development and pathogenesis of these diseases. The canonical nine-residue loop of BBIs/STH-1 provides an ideal template for drug design of specific inhibitors to target their respective proteases. 相似文献
4.
Qipan Deng ;Lindsey Becker ;Xiaodong Ma ;Xiaoming Zhong ;Ken Young ;Kenneth Ramos ;and Yong Li 《分子细胞生物学报》2014,(3):198-205
The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Significant progress has been made to discern the im- portance of p53 in coordinating cellular responses to DNA damage, oncogene activation, and other stresses. Noncoding RNAs are RNA molecules functioning without being translated into proteins. In this work, we discuss the dichotomy of p53 regulation by noncoding RNAs with four unconventional questions. First, is overexpression of microRNAs responsible for p53 inactivation in the absence of p53 mutation? Second, are there somatic mutations in the noncoding regions of the p53 gene? Third, is there a germline mutant in the non- coding regions of the p53 gene that predisposes carriers to cancer? Fourth, can p53 activation mediated by a noncoding RNA mutation cause cancer? This work highUghts the prominence of noncoding RNAs in p53 dysregutation and tumorigenesis. 相似文献
5.
The mutation-mediated overexpression of epidermal growth factor receptor tyrosine kinase(EGFR TK)and its activation play an important role in the cellular proliferation and epithelial tumorigenesis.A series of inhibitors targeting the intracellular tyrosine kinase(TK)domain of EGFR have been developed and applied to clinical practice.Although these inhibitors safely and effectively restrain tumor cell proliferation and prolong survival in some patients,acquired resistance ultimately arises.DNA mutations contribute to druginduced cancer-cell resistance. 相似文献
6.
《中国科学:生命科学英文版》2017,(7)
Tuberous sclerosis complex(TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children(7.00±5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children.The earliest manifestations of TSC were skin lesions(80% of patients) and seizures(75%). Fourteen of the children presented with retinal hamartomas, and 2 of these underwent eye enucleation at other hospitals through misdiagnosis. On magnetic resonance imaging, 18 children exhibited subependymal nodules, and 16 ones showed cortical nodules. 5 cases of non-renal hamartomas, 5 cases of multiple renal cysts, and 5 cases of cardiac rhabdomyomas were observed.The genotyping of TSC1 and TSC2 in 14 children revealed 11 with mutations in TSC2, 2 with mutations in TSC1, and no mutations of either gene in one patient. Eight of these observed mutations are reported here in for the first time. The illness presentations of the TSC2-mutated patients were more severe than that of patients carrying TSC1 mutations.There were differences in the mutations of TSC genes in Chinese children from those reported in other countries. The described clinical characteristics and genotyping will help pediatric neurologists to understand, diagnosis, and treat TSC. 相似文献
7.
Kristian Tveten Trine Ranheim Knut Erik Berge Trond P. Leren Mari Ann Kulseth 《Acta biochimica et biophysica Sinica》2009,(3):246-255
The low-density lipoprotein receptor (LDLR) mediates cholesterol homeostasis through endocytosis of lipoprotein particles, particularly low-density lipoproteins (LDLs). Normally, the lipoprotein particles are released in the endosomes and the receptors recycle to the cell surface. Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the gene encoding the LDLR. These mutations are divided into five functional classes where Class 5 mutations encode receptors that suffer from ligand-induced degradation and recycling deficiency. The aim of this study was to investigate whether it is possible to prevent the fast ligand-induced degradation of Class 5-mutant LDLR and to restore its ability to recycle to the cell surface. E387K is a naturally occurring Class 5 mutation found in FH patients, and in the present study, we used Chinese hamster ovary cells transfected with an E387K-mutant LDLR. Abrogation of endosomal acidification by adding bafdomycin A1 or addition of the irreversible serine protease inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF) and 3,4-dichloroisocoumarin (DCI), prevented the degradation of the E387K-mutant LDLR. However, the undegraded receptor did not recycle to the cell surface in the presence of LDL. Unexpectedly, AEBSF caused aggregation of early endosome antigen-1positive endosomes and the intracellular trapped LDLR co-localized with these aggregated early endosomes. 相似文献
8.
HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics 总被引:16,自引:0,他引:16
Histone deacetylases (HDACs) and histone acetyl transferases (HATs) are two counteracting enzyme families whose enzymatic activity controls the acetylation state of protein lysine residues, notably those contained in the N-terminal extensions of the core histones. Acetylation of histones affects gene expression through its influence on chromatin conformation. In addition, several non-histone proteins are regulated in their stability or biological function by the acetylation state of specific lysine residues. HDACs intervene in a multitude of biological processes and are part of a multiprotein family in which each member has its specialized functions. In addition, HDAC activity is tightly controlled through targeted recruitment, protein-protein interactions and post-translational modifications. Control of cell cycle progression, cell survival and differentiation are among the most important roles of these enzymes. Since these processes are affected by malignant transformation, HDAC inhibitors were developed as antineoplastic drugs and are showing encouraging efficacy in cancer patients. 相似文献
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11.
Marko-Varga G Fehniger TE Rezeli M Döme B Laurell T Végvári A 《Journal of Proteomics》2011,74(7):982-992
Lung cancer is a common cause of cancer mortality in the world, largely due to the risk factor of tobacco smoking. The drug therapy at the molecular level includes targeting the epidermal growth factor receptor (EGFR) tyrosine kinase activity by using inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa). The heterogeneity of disease phenotypes and the somatic mutations presented in patient populations have a great impact on the efficacy of treatments using targeted personalized medicine. In this study, we report on basic physical and chemical properties of erlotinib and gefitinib in three different lung cancer tumor phenotypes, using MALDI instrumentation in imaging mode, providing spatial localization of drugs without chemical labeling. Erlotinib and gefitinib were analyzed in i) planocellular lung carcinoma, ii) adenocarcinoma and iii) large cell lung carcinoma following their deposition on the tissue surfaces by piezo-dispensing, using a controlled procedure. The importance of high-resolution sampling was crucial in order to accurately localize the EGFR tyrosine kinase inhibitors deposited in heterogeneous cancer tissue compartments. This is the first report on personalized drug characterization with localizations at a lateral resolution of 30μm, which allowed us to map these compounds at attomolar concentrations within the lung tumor tissue microenvironments. 相似文献
12.
Michael J. Eck Cai-Hong Yun 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(3):559-566
EGFR and other ErbB-family tyrosine kinases are overexpressed in many human tumors, and their aberrant expression and mutational activation is associated with the development, progression and aggressiveness of a number of malignancies. Thus the EGFR kinase has long been recognized as a potential drug target in oncology, and small-molecule inhibitors have been under development for more than two decades. As a result of their effectiveness in treating non-small cell lung cancers (NSCLCs) driven by somatic mutations in the EGFR kinase, gefitinib and erlotinib were the first EGFR tyrosine kinase inhibitors (TKIs) approved for clinical use. Ironically, these drugs found their target against mutant forms of the EGFR kinase, which have altered enzyme active sites, and not against the wild type (WT) kinase against which their potency and selectivity was carefully honed. Here we review recent structural and enzymological studies that explore the exquisite sensitivity of a subset of these lung cancer mutants to gefitinib and erlotinib. We discuss available structural evidence for the mechanisms of activation of the EGFR kinase by these mutants, and compare it to physiologic activation of the kinase by ligand-induced dimerization. Finally, we consider the mechanisms by which the secondary T790M “gatekeeper” mutation confers resistance to gefitinib and erlotinib. 相似文献
13.
Han W Pan H Chen Y Sun J Wang Y Li J Ge W Feng L Lin X Wang X Wang X Jin H 《PloS one》2011,6(6):e18691
Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer. 相似文献
14.
Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors
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Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non‐small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP. However, patients who were treated with the erlotinib and gefitinib will relapse because of the emergence of drug‐resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. In order to overcome drug resistance, Pharmaceutical chemistry experts recently devoted great endeavors to the development of second‐generation irreversible selective inhibitors which covalently modify Cys797 or Cys773 at the ATP binding cleft. Nevertheless, these inhibitors have not reached ideal effect of experts in patients with T790M positive mutation and apparently because of the dose‐limiting toxicities associated with inhibition of wild type EGFR. A novel class of ‘third generation’ EGFR TKIs have been developed that is sensitising and T790M mutant‐specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Herein, we provides an overview of the second and third generation inhibitors currently approved, in clinical trial and also encompasses novel structures of discovery. This review mainly focuses on drug resistance, their mechanisms of action, development of structure–activity relationships and binding modes. 相似文献
15.
Pao W Miller VA Politi KA Riely GJ Somwar R Zakowski MF Kris MG Varmus H 《PLoS medicine》2005,2(3):e73
BackgroundLung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of “acquired” resistance.ConclusionIn patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers. 相似文献
16.
Di Maio M Gridelli C Normanno N Perrone F Ciardiello F 《Journal of cellular physiology》2005,205(3):355-363
Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown promising activity in patients with non-small cell lung cancer (NSCLC). Gefitinib has been the first of these drugs to be licensed for third-line treatment of advanced NSCLC patients. More recently, erlotinib has been shown to be more effective than placebo in increasing overall survival (OAS) and has been approved for NSCLC patients after failure of chemotherapy. However, a large body of clinical and experimental evidence suggests that the benefit from these drugs is limited to a subgroup of patients. The availability of clinical or molecular criteria for predicting sensitivity to EGFR-TKIs is the most relevant issue for their correct use and for planning future research. Determination of EGFR expression is not sufficient to predict sensitivity to EGFR-TKIs. However, several clinical features (female gender, adenocarcinoma/bronchioloalveolar histotype, never-smoking status, Oriental Asian origin) are associated with major clinical responses. The identification of somatic mutations in the tyrosine kinase domain of the EGFR gene represents the most important molecular marker of sensitivity to EGFR-TKIs. These "activating" mutations can be found in a high proportion of gefitinib- or erlotinib-responding patients. However, clinical effectiveness might not be limited to patients carrying EGFR mutations, in which the objective response is probably the detectable effect of apoptosis induction in cancer cells. In fact, clinical efficacy with gefitinib or erlotinib is also observed in another subgroup of patients, in which a tumor growth delay, determined by a block in cancer cell proliferation, could induce a prolonged and clinically relevant disease stabilization. 相似文献
17.
Marzena Anna Lewandowska Karol Czubak Katarzyna Klonowska Wojciech Jozwicki Janusz Kowalewski Piotr Kozlowski 《PloS one》2015,10(2)
Lung cancer is the leading cause of cancer-related death worldwide. Recent progress in lung cancer diagnosis and treatment has been achieved due to a better understanding the molecular mechanisms of the disease and the identification of biomarkers that allow more specific cancer treatments. One of the best known examples of personalized therapy is the use of tyrosine kinase inhibitors, such as gefitinib and erlotinib, for the successful treatment of non-small-cell lung cancer patients selected based on the specific EGFR mutations. Therefore, the reliable detection of mutations is critical for the application of appropriate therapy. In this study, we tested a two-tiered mutation detection strategy using real-time PCR assays as a well-validated high-sensitivity method and multiplex ligation-dependent probe amplification (MLPA)-based EGFRmut+ assay as a second-tier standard-sensitivity method. One additional advantage of the applied MLPA method is that it allows the simultaneous detection of EGFR mutations and copy-number alterations (i.e., amplifications) in EGFR, MET and ERBB2. Our analysis showed high concordance between these two methods. With the use of this two-tier strategy, we reliably determined the frequency of EGFR mutations and EGFR, MET and ERBB2 amplifications in over 200 lung cancer samples. Additionally, taking advantage of simultaneous copy number and small mutation analyses, we showed a very strong correlation between EGFR mutations and EGFR amplifications and a mutual exclusiveness of EGFR mutations/amplifications with MET and ERBB2 amplifications. Our results proved the reliability and usefulness of the two-tiered EGFR testing strategy. 相似文献
18.
Jingheng Ning Qi Wu Zhenguo Liu Jianhui Wang 《Journal of receptor and signal transduction research》2016,36(1):37-44
Human epidermal growth factor receptor (EGFR) has become a well-established target for the treatment of non-small cell lung cancer (NSCLC). However, a large number of in-frame deletion, insertion and duplication mutations in the EGFR tyrosine kinase (TK) domain have been observed to alter drug response to such a kinase target. Thus, a systematic investigation of the intermolecular interactions between the clinical small-molecule agents and various EGFR in-frame mutants would help to establish a complete picture of drug response to kinase mutations in lung cancer, and to design new EGFR inhibitors with high potency and selectivity to target drug-resistant mutants. Here, we describe a combined pipeline to explore the drug response of five representative EGFR inhibitors, including three FDA-approved agents (gefitinib, erlotinib and lapatinib) and two compounds under clinical development (AEE788 and TAK-285) to a number of clinically relevant EGFR in-frame mutations, aiming at a comprehensive understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity to EGFR in-frame mutations. It was found that the insertion and duplication mutations in exon 20 can generally cause drug resistance to EGFR due to the reduced size of kinase’s active pocket, while deletion mutations in exon 19 associate closely with increased inhibitor sensitivity to EGFR by establishing additional non-bonded interactions across complex interface, including hydrogen bonds, cation–π interactions and hydrophobic contacts. 相似文献
19.
Sato T Watanabe H Tsuganezawa K Yuki H Mikuni J Yoshikawa S Kukimoto-Niino M Fujimoto T Terazawa Y Wakiyama M Kojima H Okabe T Nagano T Shirouzu M Yokoyama S Tanaka A Honma T 《Bioorganic & medicinal chemistry》2012,20(12):3756-3767
EGFR is a target protein for the treatment of non small cell lung cancer (NSCLC). The mutations associated with the activation of EGFR kinase activity, such as L858R and G719S, destabilize the inactive conformation of EGFR and are closely linked with the development of NSCLC. The additional T790M mutation reportedly causes drug resistance against the commercially available EGFR inhibitors, gefitinib and erlotinib. In this study, we searched for novel G719S/T790M EGFR inhibitors by a new in silico screening strategy, using two datasets. The results of in silico screening using protein-ligand docking are affected by the selection of 3D structure of the target protein. As the first strategy, we chose the 3D structures for in silico screening by test dockings using the G719S/T790M crystal structure, its molecular dynamics snapshots, and known inhibitors of the drug-resistant EGFR. In the second strategy, we selected the 3D structures by test dockings using all of the EGFR structures, regardless of the mutations, and all of the known EGFR inhibitors. Using each of the 3D structures selected by the strategies, 1000 compounds were chosen from the 71,588 compounds. Kinase assays identified 15 G719S/T790M EGFR inhibitors, including two compounds with novel scaffolds. Analyses of their structure-activity relationships revealed that interactions with the mutated Met790 residue specifically increase the inhibitory activity against G719S/T790M EGFR. 相似文献
20.
Do‐Young Choi Sungyong You Jae Hun Jung Jae Cheol Lee Jin Kyung Rho Kye Young Lee Michael R. Freeman Kwang Pyo Kim Jayoung Kim 《Proteomics》2014,14(16):1845-1856
Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs), including gefitinib, are the first‐line treatment of choice for nonsmall cell lung cancer patients who harbor activating EGFR mutations, however, acquired resistance to EGFR‐TKIs is inevitable. The main objective of this study was to identify informative protein signatures of extracellular vesicles (EV) derived from gefitinib‐resistant nonsmall cell lung cancer cells using proteomics analysis. Nano‐LC–MS/MS analysis identified with high confidence (false discovery rate < 0.05, fold change ≥2) 664 EV proteins enriched in PC9R cells, which are resistant to gefitinib due to EGFR T790M mutation. Computational analyses suggested components of several signal transduction mechanisms including the AKT (also PKB, protein kinase B)/mTOR (mechanistic target of rapamycin) pathway are overrepresented in EV from PC9R cells. Treatment of recipient cells with EV harvested from PC9R cells increased phosphorylation of signaling molecules, and enhanced proliferation, invasion, and drug resistance to gefitinib‐induced apoptosis. Dose‐ and time‐dependent pharmaceutical inhibition of AKT/mTOR pathway overcame drug resistance of PC9R cells and those of H1975 exhibiting EGFR T790M mutation. Our findings provide new insight into an oncogenic EV protein signature regulating tumor microenvironment, and will aid in the development of novel diagnostic strategies for prediction and assessment of gefitinib resistance. 相似文献