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Protein phosphorylation pathways disruption by pesticides

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Advances in Biological Chemistry 2013年第5期3卷 460-474页

作者： Gladis Magnarelli Teresa Fonovich Escuela de Ciencia y Tecnología Universidad Nacional de San Martín Buenos Aires Argentina Instituto Multidisciplinario de Investigación y Desarrollo de la Patagonia Norte (IDEPA) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad Nacional del Comahue Neuquén Argentina Facultad de Ciencias Médicas Universidad Nacional del Comahue Cipolletti Argentina

Phosphosites in the human proteome represent an excellent source of potential biomarkers of pesticide toxicity. In fact, experimental animal models as well as in vitro studies have revealed phosphorylation disruption associated to metabolic regulation, hormone signaling, neuronal function and differentiation, cell survival and death. Due to their estrogen-mimicking ability, pesticides are considered as prime etiological suspects of increasing tumor incidence. Evidences of alterations in the signal transduction pathways involved in the tumor progression stage of pesticides were also provided. Despite progress in understanding the effect of pesticides on the human phosphorproteome and their health outcomes, it remains a complex issue to be studied. By now, the potential impact of pesticides in epigenetic phosphorylation pathways remains poorly explored. In addition, studies involving pesticides mixtures effects are needed. This review updates and provides a comprehensive discussion on the molecular and biochemical events underlying protein phosphorylation pathway disruption caused by pesticides most frequently detected in human tissues and fluids, such as organochlorine pesticides and organophosphates. The link between epidemiological studies and experimental approaches is also considered. Future challenges, such as micro-array phosphoproteome studies to complement gene expression arrays to understand the mechanisms involved in pesticide toxicology are briefly discussed.

关键词： Protein Phosphorylation Organochlorine Pesticides Organophosphate Pesticides kinases

A mechanism underlying stimulation and inhibition of protein kinase C by lyso-PC: A role of membrane physical state

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Science China(Life Sciences) 1998年第6期41卷 584-591页

作者：潘最陈建文

Lysophosphatidylcholine (lyso PC) biphasically regulates the diacylglycerol induced activation of protein kinase C (PKC). In common parlance, lyso PC stimulates PKC at low concentrations, but, conversely, inhibits it at high concentrations. The activity of purified PKC from rat brains was measured in the vesicles made up of dipalmitoylphosphatidylserine (DPPS), 1,2 sn diolein (DOG) and different molar ratios of 1 palmitoyl sn glycerol 3 phosphoryl choline (C16:0 lyso PC). The effect, i.e. stimulation or inhibition on PKC by C16:0 lyso PC, depends on DPPS and DOG concentrations as well as its own concentration. When the concentration of DOG is stable, this C16:0 lyso PC action depends on C16:0 lyso PC/DPPS molar ratio. Differential scanning calorimetry (DSC), two fluorescence probes and light scattering were used to analyze the physical characteristics of membrane, including thermotropic phase behavior, the turbidity, the lipid molecular acyl chains packing and the head group spacing. The more adulteration of C16:0 lyso PC in liposome bilayer membrane, the looser acyl chains pack, and the broader head group spacing. DSC results show that there are two immiscible lipid areas in the membrane: C16:0 lyso PC rich area and C16:0 lyso PC poor area. When C16:0 lyso PC/DPPS molar ratio was 0 234, the two areas had the broadest boundary and the activation of PKC was the highest. When the ratio was over 0 434, the phase transition of DPPS disappeared; micelle tended to substitute the structure of bilayer; the activity of PKC was inhibited completely. DOG can stabilize the bilayer structure of membrane, so the C16:0 lyso PC/DPPS molar ratios to inhibit PKC in lipid mixture with DOG are higher than that without DOG. The ability of C16:0 lyso PC to change the physical properties and the structure of membrane plays an important role in its effect on PKC activation.

关键词： protein kinases C lysophosphatidylcholine diolein differential scanning calorimetry physical properties of membrane.

Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein

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Journal of Behavioral and Brain Science 2018年第2期8卷 77-92页

作者： Javed Iqbal College of Life Science Shaanxi Normal University Xi’an China

Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions;by which mechanisms it promotes neurite outgrowth;and how it protects the brain from Alzheimer disease (AD).

关键词： Learning and Memory TTR—Transthyretin AD—Alzheimer Disease CSF—Cerebrospinal Fluid MAPK—Mitogen-Activated Protein kinases CREB—cAMP Response Element Binding Protein ERK—Extracellular Receptor kinases Aβ—Amyloid Beta LTP—Long-Term Potentiation LTD—Long-Term Depression

Recent advances in the molecular mechanism of Janus kinase activation

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Journal of Translational Neuroscience 2018年第4期3卷 15-20页

作者： Yukun Han Jianliang Zhang Department of Neurobiology Beijing Institute for Brain Disorders Capital Medical University Beijing 100069 China Key Laboratory for Neurodegenerative Disease of the Ministry of Education Beijing Key Laboratory of Neural Regeneration and Repair Beijing 100069 China

The JAK (Janus kinase) family members play a role in the transmission of signals from extracellular stimuli across the plasma membrane via the cytoplasm to the nucleus in eukaryotes. The JAK family is comprised of JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), and the complexities underlying their activation and regulation are still being investigated. Here, we review the recent advances of their functions and the underlying mechanism of activation. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the JAK proteins, as well as the mechanism of JAK activation, particularly the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain’s catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by phosphatase and SH2 (Src homology 2) domain-containing proteins. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and shed much light on the potential novel strategies for precise treatment of the associated diseases.

关键词： Janus kinase (JAK) neuroinflammation non-receptor tyrosine kinases neurodegeneration

Current Perspectives on Sunitinib Targeted Therapy for Tumors

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Journal of Cancer Therapy 2011年第4期2卷 535-541页

作者： Karolin Kamel Abdel-Aziz 不详

This review highlights therapeutic agents from recent cancer therapeutic trials showing the greatest potential for further clinical use for sunitinib in the near future. In fact, sunitinib is one of multi-tyrosine kinase inhibitors;tyrosine kinases are enzymes, which transfer phosphate groups from ATP to the hydroxyl group of tyrosine residues on signal transduction molecules. Phosphorylation of signal transduction molecules, in turn, induces dramatic changes in tumor growth, including activation of angiogenesis and DNA synthesis. Therefore, sustain efforts have been directed for developing inhibitors for angiogenesis, which is the marginal process for tumor growth and development through targeting TKs. Almost if not all angiogenesis inhibitors target the vascular endothelial growth factor (VEGF) signaling pathway.

关键词： Platelet-Derived Growth Factor (PDGF) Cytochrome P450 Enzyme (CYP3A4) Dose-Limiting Toxicities (DLTs) Hepatocyte Growth Factor (HGF) Tyrosine kinases (TKs)

Isoleucine, an Essential Amino Acid, Induces the Expression of Human <i>β</i>Defensin 2 through the Activation of the G-Protein Coupled Receptor-ERK Pathway in the Intestinal Epithelia

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Food and Nutrition Sciences 2012年第4期3卷 548-555页

作者： Youkou Konno Toshifumi Ashida Yuhei Inaba Takahiro Ito Hiroki Tanabe Atsuo Maemoto Tokiyoshi Ayabe Yusuke Mizukami Mikihiro Fujiya Yutaka Kohgo Division of Gastroenterology and Hematology/Oncology Department of Medicine Asahikawa Medical University Asahikawa Japan IBD Center Sapporo Higashi Tokushukai Hospital Sapporo Japan Innate Immunity Laboratory Department of Cellular Life Science Faculty of Advanced Life Science Hokkaido University Sapporo Japan

Anti-microbial peptides are essential for the intestinal innate immunity that protects the intestinal epithelia from attacks by foreign pathogens. Human β-defensin (HBD) is one of the pivotal anti-microbial peptides that are expressed in the colonic epithelia. This study investigated the effect and the signaling mechanism of inducible β-defensin HBD2 by an essential amino acid, isoleucine (Ile) in colonic epithelial cells. Here we examined the expression level of HBD2 on induction of Ile in epithelial cells, and checked this pathway. HBD2 mRNA was induced by co-incubation with IL-1α and Ile in Caco2 cells, but not by Ile alone. An inhibitor of either ERK or Gi, a subunit of G-proteins, reduced the induction of HBD2 mRNA by Ile. The treatment with Ile also increased the intracellular calcium ion concentration, thus suggesting that the GPCR and ERK signaling pathway mediate the effects of Ile. These results indicate that an essential amino acid, Ile, enhances the expression of an inducible β-defensin, namely HBD2, by IL-1α through the activation of GPCRs and ERK signaling pathway. The administration of Ile may therefore represent a possible option to safely treat intestinal inflammation.

关键词： Isoleucine Human β-Defensin G-Protein Coupled Receptor Extracellular Signal-Regulated kinases Pathway Inflammatory Bowel Disease Crohn’s Disease

Detection of Sugar-Regulated Gene Expression and Signaling in Suspension-Cultured Rice Cells

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American Journal of Plant Sciences 2018年第6期9卷 1124-1142页

作者： Shin-Lon Ho Department of Agronomy National Chiayi University Chiayi Taiwan

To better understand the mechanism of sugar signaling in rice cell, the suspension-cultured rice cells were transferred from sucrose-containing (+S) to sucrose-free (-S) of MS culture medium, we found that ribosomal RNAs (rRNAs) were degraded progressively. This suggests that carbon, nitrogen, and phosphate were recycled in this process and the reduction in cellular rRNAs might lead to decreased translation to save energy in response to sugar starvation. Differential screening revealed that two groups of genes, sugar-starvation-repressed (SSR) and sugar-starvation-activated (SSA) genes, were regulated by sugar in an opposing manner. Northern-blot analysis showed that two major hybridization signals of 0.8 and 1.9 kb were induced strongly under sugar starvation. The two populations of genes corresponded with homologs of α-amylases (1.9 kb) and the glycine-rich proteins (GRPs) gene family (0.8 kb), and all were SSA genes. Expression of GRP genes was strongly induced in sugar-starved cells, which suggests that GRPs may help to protect cells against nutritional stress. Treatment of +S and -S cells with the protein kinase (PK) inhibitor staurosporine (St) and the serine/theronine phosphoprotein phosphatases 1 (PP1) and 2A (PP2A) inhibitor okadaic acid (OA) revealed that PP1 and PP2A (PPs) might be involved in increasing SSR gene expression in +S cells, and that activation of the majority of the SSA genes in -S cells might be due to PKs activity. These results suggested that PKs and PPs might be involved in the sugar regulation of SSR and SSA gene expression. An in-gel PK activity assay demonstrated that the activity of two classes of PKs (50 and 66 kDa) may be induced rapidly after transfer of +S cells to -S medium. Following transfer of -S cells to +S medium, a novel class of 38 kDa PK was induced rapidly and showed high activity. The 38 kDa PK might play a role in sugar sensing, and the 50 and 66 kDa PKs might play roles in signal sensing under sugar starvation in rice cells. These results provide valuable informati

关键词： Suspension-Cultured Rice Cells Glycine-Rich Proteins Sugar-Starvation Repressed Sugar-Starvation Activated Protein kinases Phosphoprotein Phosphatases

Evaluation of CDK6 and p16/INK4a-Derived Peptides Interaction

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Computational Molecular Bioscience 2013年第3期3卷 53-57页

作者： Andrey Kazennov Andrey Alekseenko Vladimir Bozhenko Tatiana Kulinich Nikolay Shuvalov Yaroslav Kholodov Department of Computational Mathematics Moscow Institute of Physics and Technology Dolgoprudny Russia Russian Scientific Center of Roentgenoradiology Moscow Russia

The goal of this work is the development of novel peptides with high efficacy of inhibiting activity of CDK6/CyclinD complex. The peptides were derived from primary sequence of P16 protein and its homologues. The interactions between CDK6 and P16/INK4a-derived peptides are studied with molecular dynamics simulation employing umbrella sampling method. The SASA implicit solvent model was used for simulation, which was accelerated using NVIDIA GPUs.

关键词： Cyclin-Dependent kinases Molecular Dynamics Umbrella Sampling GPU SASA

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EphA2与恶性肿瘤关系研究新进展

广东医学 2008年第8期29卷 1417-1419页

作者：张平袁红纲董自强三峡大学第一临床医学院泌尿外科湖北宜昌443003

EphA2是一个跨膜酪氨酸激酶受体，属于酪氨酸激酶受体（receptor tyrosine kinases，RTKs）超家族成员之一。EphA2通常以相对较低的水平表达在成人各种上皮细胞中，其在介导相应的信息传递过程中起着关键性的作用，调控着许多方面的细... 详细信息

EphA2是一个跨膜酪氨酸激酶受体，属于酪氨酸激酶受体（receptor tyrosine kinases，RTKs）超家族成员之一。EphA2通常以相对较低的水平表达在成人各种上皮细胞中，其在介导相应的信息传递过程中起着关键性的作用，调控着许多方面的细胞行为。近来研究显示，EphA2在多种肿瘤组织中高表达，进一步的研究证实EphA2过表达促进肿瘤向恶性发展。因其在正常及肿瘤组织中表达的差异性，加之其有别于其他RTKs的结构及功能的特异性，目前EphA2被认为是一个很有潜力的靶点，正成为各种肿瘤防治研究的焦点。在此，笔者就目前对EphA2的了解及其在癌症相关研究中的进展加以综述。

关键词： EphA2 肿瘤关系跨膜酪氨酸激酶受体恶性 kinases 肿瘤组织家族成员上皮细胞