The synthesis of proteins in unnucleated blood platelets
23 Jul 2013-Postȩpy higieny i medycyny doświadczalnej (Postepy Hig Med Dosw (Online))-Vol. 67, pp 672-679
TL;DR: A detailed overview of platelet protein synthesis can be found in this paper, where the authors present the molecular mechanisms of protein synthesis in activated platelets (and synthesis of the most important platelet proteins).
Abstract: Platelets are the smallest, unnucleated blood cells that play a key role in maintaining normal hemostasis. In the human body about 1x1011 platelets are formed every day, as a the result of complex processes of differentiation, maturation and fragmentation of megakaryocytes. Studies done over 4 decades ago demonstrated that circulating in blood mature platelets can synthesize proteins. Recent discoveries confirm protein synthesis by unnucleated platelets in response to activation. Moreover, protein synthesis alters the phenotype and function of platelets. Platelets synthesize several proteins involved in hemostasis (COX, αIIbβ3, TF PAI-1, Factor XI, protein C inhibitor) and in inflammatory process (IL-1β, CCL5/RANTES). In spite of lack of transcription platelets have a stable mRNA transcripts with a long life correlated with platelet life span. Platelets also show expression of two important key regulators of translation eIF4E and EIF-2α and have a variety of miRNA molecules responsible for translational regulation. This article describes the historical overview of research on protein synthesis by platelets and presents the molecular mechanisms of protein synthesis in activated platelets (and synthesis of the most important platelet proteins).
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TL;DR: The analysis of platelet function capability in MS could provide useful information for studying the pathogenesis of this disease and medication must be multifaceted and blood platelets can probably be identified as new targets for therapy in the future.
Abstract: The available data, including experimental studies, clearly indicate an excessive intravascular activation of circulating platelets in multiple sclerosis (MS) and their hyper-responsiveness to a variety of physiological activators. Platelet activation is manifested as an increased adhesion and aggregation and is accompanied by the formation of pro-thrombotic microparticles. Activated blood platelets also show an expression of specific membrane receptors, synthesis many of biomediators, and generation of reactive oxygen species. Epidemiological studies confirm the high risk of stroke or myocardial infarction in MS that are ischemic incidents, strictly associated with incorrect platelet functions and their over pro-thrombotic activity. Chronic inflammation and high activity of pro-oxidative processes in the course of MS are the main factors identified as the cause of excessive platelet activation. The primary biological function of platelets is to support vascular integrity, but the importance of platelets in inflammatory diseases is also well documented. The pro-thrombotic activity of platelets and their inflammatory properties play a part in the pathophysiology of MS. The analysis of platelet function capability in MS could provide useful information for studying the pathogenesis of this disease. Due to the complexity of pathological processes in MS, medication must be multifaceted and blood platelets can probably be identified as new targets for therapy in the future.
26 citations
TL;DR: Research described in this review clearly indicate that polyphenols and polyphenol-rich extracts possess not only antioxidative but also anticoagulant properties and may be useful in creation of new therapeutic agents or dietary supplements.
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TL;DR: This review summarizes recent insights in the platelet activation accompanied by the exocytosis of bioactive compounds stored in granules, formation of platelet microparticles, expression of specific membrane receptors, synthesis of numerous biomediators, generation of free radicals, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of multiple sclerosis.
Abstract: Increasing evidence indicates that blood platelets contribute to diverse processes that extend beyond hemostasis. Many of the same mechanisms that play a role in hemostasis and thrombosis facilitate platelets the participation in other physiological and pathological processes, particularly in the inflammation, the immune response and central nervous system disorders. Platelets are involved in pathophysiology of central nervous system diseases, especially in the pathogenesis of multiple sclerosis, but their role appears to be neglected. Platelets contribute to the inflammation and cooperate with immune cells in inflammatory and immune responses. These blood cells were identified in inflamed spinal cord and in the brain in chronic active lesions of multiple sclerosis and in the related animal models referred as Experimental Autoimmune Encephalomyelitis. This review summarizes recent insights in the platelet activation accompanied by the exocytosis of bioactive compounds stored in granules, formation of platelet microparticles, expression of specific membrane receptors, synthesis of numerous biomediators, generation of free radicals, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of multiple sclerosis. Understanding the role of platelets in multiple sclerosis may be essential for improved therapies.
24 citations
TL;DR: It is established that three major flavonolignans: silybin, silychristin and silydianin, in concentrations of up to 100 µM, have neither a cytotoxic nor genotoxic effect on blood platelets, PMBCs and A549, and that they actually protect cellular mitochondria.
Abstract: Flavonolignans are the main components of silymarin, which represents 1.5–3% of the dry fruit weight of Milk thistle (Silybum marianum L. Gaernt.). In ancient Greece and Romania, physicians and herbalists used the Silybum marianum to treat a range of liver diseases. Besides their hepatoprotective action, silymarin flavonolignans have many other healthy properties, such as anti-platelet and anti-inflammatory actions. The aim of this study was to evaluate the toxic effect of flavonolignans on blood platelets, peripheral blood mononuclear cells (PBMCs) and human lung cancer cell line—A549—using different molecular techniques. We established that three major flavonolignans: silybin, silychristin and silydianin, in concentrations of up to 100 µM, have neither a cytotoxic nor genotoxic effect on blood platelets, PMBCs and A549. We also saw that silybin and silychristin have a protective effect on cellular mitochondria, observed as a reduction of spontaneous mitochondrial DNA (mtDNA) damage in A549, measured as mtDNA copies, and mtDNA lesions in ND1 and ND5 genes. Additionally, we observed that flavonolignans increase the blood platelets’ mitochondrial membrane potential and reduce the generation of reactive oxygen species in blood platelets. Our current findings show for the first time that the three major flavonolignans, silybin, silychristin and silydianin, do not have any cytotoxicity and genotoxicity in various cellular models, and that they actually protect cellular mitochondria. This proves that the antiplatelet and anti-inflammatory effect of these compounds is part of our molecular health mechanisms.
24 citations
TL;DR: The effects of three major flavonolignans (silybin, silychristin and silydianin) on ADP-induced blood platelet activation using the flow cytometry analysis as well as determine the mechanism of this interaction by bioinformatic ligand docking method.
21 citations
References
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TL;DR: Both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis are described.
Abstract: The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.
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TL;DR: Possible mechanisms by which miRNAs control translation and mRNA degradation are discussed, an emerging theme is that mi RNAs, and siRNAs to some extent, target m RNAs to the general eukaryotic machinery for mRNA degradation and translation control.
Abstract: The control of translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs control translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and translation control.
2,030 citations
TL;DR: Inhibition of β3 integrin engagement markedly attenuated the synthesis of IL-1β, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects.
Abstract: Platelets release preformed mediators and generate eicosanoids that regulate acute hemostasis and inflammation, but these anucleate cytoplasts are not thought to synthesize proteins or cytokines, or to influence inflammatory responses over time. Interrogation of an arrayed cDNA library demonstrated that quiescent platelets contain many messenger RNAs, one of which codes for interleukin 1β precursor (pro–IL-1β). Unexpectedly, the mRNA for IL-1β and many other transcripts are constitutively present in polysomes, providing a mechanism for rapid synthesis. Platelet activation induces rapid and sustained synthesis of pro–IL-1β protein, a response that is abolished by translational inhibitors. A portion of the IL-1β is shed in its mature form in membrane microvesicles, and induces adhesiveness of human endothelial cells for neutrophils. Signal-dependent synthesis of an active cytokine over several hours indicates that platelets may have previously unrecognized roles in inflammation and vascular injury. Inhibition of β3 integrin engagement markedly attenuated the synthesis of IL-1β, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects.
677 citations
TL;DR: Signal-dependent splicing is a novel function of platelets that demonstrates remarkable specialization in the regulatory repertoire of this anucleate cell and suggests previously unrecognized diversity regarding the functional roles of the spliceosome in eukaryotic cells.
607 citations
TL;DR: It is shown that human platelets harbor an abundant and diverse array of microRNAs (miRNAs), which are known as key regulators of mRNA translation in other cell types and lends an additional level of complexity to the control of gene expression in these anucleate elements of the cardiovascular system.
Abstract: Platelets have a crucial role in the maintenance of hemostasis as well as in thrombosis and vessel occlusion, which underlie stroke and acute coronary syndromes. Anucleate platelets contain mRNAs and are capable of protein synthesis, raising the issue of how these mRNAs are regulated. Here we show that human platelets harbor an abundant and diverse array of microRNAs (miRNAs), which are known as key regulators of mRNA translation in other cell types. Further analyses revealed that platelets contain the Dicer and Argonaute 2 (Ago2) complexes, which function in the processing of exogenous miRNA precursors and the control of specific reporter transcripts, respectively. Detection of the receptor P2Y(12) mRNA in Ago2 immunoprecipitates suggests that P2Y(12) expression may be subjected to miRNA control in human platelets. Our study lends an additional level of complexity to the control of gene expression in these anucleate elements of the cardiovascular system.
443 citations