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Diadenosine Oligophosphates (Apna), a Novel Class of Signalling Molecules?

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Diadenosine Oligophosphates (Apna), a Novel Class of Signalling Molecules? View metadata,FEBS 20186 citation and similar papers at core.ac.uk FEBS Letters 427 (1998)brought to 157^163 you by CORE provided by Elsevier - Publisher Connector Minireview Diadenosine oligophosphates (ApnA), a novel class of signalling molecules? Lev L. Kisseleva;b;*, Just Justesenc, Alexey D. Wolfson1;d, Lyudmila Yu. Frolovaa;b aU248 INSERM, Institut Curie, Paris, France bEngelhardt Institute of Molecular Biology, 117984 Moscow, Russia cInstitute of Molecular and Structural Biology, University of Aarhus, Aarhus, Denmark dDepartment of Biochemistry, University of Colorado, Boulder, CO, USA Received 24 March 1998 as pleiotropically acting alarmones [5]. Further studies dem- Abstract The diadenosine oligophosphates (ApnA) were dis- covered in the mid-sixties in the course of studies on aminoacyl- onstrated a ubiquitous occurrence of ApnA in the whole spec- tRNA synthetases (aaRS). Now, more than 30 years later, about trum of organisms from bacteria to higher eukaryotes. 300 papers have been published around these substances in Although the role of ApnA in stress response remains un- attempt to decipher their role in cells. Recently, ApnA have known for eukaryotes, in bacteria ApnA binds to and inhibit emerged as intracellular and extracellular signalling molecules the oxidative stress-related proteins [6,7]. The earlier phase of implicated in the maintenance and regulation of vital cellular ApnA investigations was summarised in several reviews [8^ functions and become considered as second messengers. Great 14]. variety of physiological and pathological effects in mammalian Till the late eighties the role of ApnA in higher eukaryotes cells was found to be associated with alterations of ApnA levels remained controversial. More recently, due to e¡orts of many (n from 2 to 6) and Ap3A/Ap4A ratio. Cell differentiation and groups, ApnA have emerged as putative low-molecular extra- apoptosis have substantial and opposite effects on Ap3A/Ap4A ratio in cultured cells. A human Ap A hydrolase, Fhit, appeared and intracellular signals implicated in the most essential cel- 3 lular functions. The aim of this review is to summarise brie£y to be involved in protection of cells against tumourigenesis. Ap3A is synthesised by mammalian u synthetase (TrpRS) which in the recent observations on the possible roles of ApnA mainly contrast to most other aaRS is unable to synthesise Ap4A and is in higher eukaryotes. an interferon-inducible protein. Moreover, Ap3A appeared to be If ApnA do play important but unknown roles in cell me- a preferred substrate for 2-5A synthetase, also interferon- tabolism, one should observe at least two phenomena: phys- inducible, priming the synthesis of 2P adenylated derivatives of iological e¡ects on various organisms, cell types, tissues, or Ap A, which in turn may serve as substrates of Fhit. Tumour 3 organs induced by ApnA in vivo and/or in vitro, and depend- suppressor activity of Fhit is assumed to be associated with ence of Ap A concentrations in various cell types or organ- involvement of the FhitWAp A complex in cytokine signalling n 3 isms on external and/or internal environmental factors and pathway(s) controlling cell proliferation. The ApnA family is potentially a novel class of signal-transducing molecules whose physiological or pathological cell status. If both of these pre- functions are yet to be determined. requisites are met, more sophisticated biochemical analysis z 1998 Federation of European Biochemical Societies. would be required to elucidate the role of these molecules in the framework of cellular regulation. Key words: Diadenosine oligophosphate; Signal transduction; Fhit; 2-5A synthetase; 2. ApnA are physiologically active and respond to various Tryptophanyl-tRNA synthetase; Tumour suppression factors Examples of the e¡ects observed with ApnA are given in 1. Introduction Table 1. Some interesting features emerge from examination of even this incomplete set of data. Many entirely di¡erent Diadenosine oligophosphates (ApnA) are made up of two tissues or cells respond to ApnA (heart, hyppocampus, sperm, adenosine moieties joined in 5P-5P linkage by a chain from two hepatocytes neutrophils, pancreatic cells, etc.) indicating the to six phosphodiester linkages. These compounds were discov- involvement of ApnA family in wide-spread biochemical ered by P. Zamecnik and his co-workers in the mid-sixties events, not restricted to any specialised cell type or tissue. (reviewed in [1]) but the ¢rst indication of the putative phys- The other important feature of ApnA e¡ects is a great variety iological role of ApnA appeared only 10 years later when a of responses that occurs in various cell types after adminis- correlation between Ap4A concentration and proliferative sta- tration or addition of ApnA (Table 1, left column). Some tus of mammalian cells has been demonstrated [2]. In prokar- e¡ects are closely associated with nuclear functions (e.g. stim- yotes, heat shock and oxidative stress cause ApnA accumula- ulation of DNA synthesis, mitogenic activity, activation of tion [3,4], and for this reason these molecules were considered gene transcription), others involve membranes (e.g. induction 2 of Ca oscillations and release, inhibition of KATP channels, etc.). Some e¡ects occur with cells and tissues as whole entities *Corresponding author. Fax: +7 (095) 135 14 05. (e.g. inhibition of sperm motility, decrease of coronary perfu- E-mail: [email protected] sion pressure, vasoconstrictor and vasodilator actions, preven- 1On leave from Bakh Institute of Biochemistry, Moscow, Russia. tion of aggregation of human platelets induced by ADP). 0014-5793/98/$19.00 ß 1998 Federation of European Biochemical Societies. All rights reserved. PII S0014-5793(98)00420-7 FEBS 20186 7-5-98 158 L.L. Kisselev et al./FEBS Letters 427 (1998) 157^163 Table 1 Examples of physiological e¡ects associated with ApnA E¡ect Target cells or tissues ApnA Reference Inhibition of KATP channels, Ki 14^17 WM Myocardium Ap4A, Ap5A, Ap6A [22] Inhibition of KATP channels, Ki 17 WM Pancreatic L cells (mice) Ap3A, Ap4A [23] High probability of KATP channel opening at Guinea-pig myocardium Ap5A [15] ischemia Activation of Egr-1 gene, mitogenic e¡ect, Cultured renal mesangial cells (rats) ApnA(n = 3^6) [24] stimulation of DNA synthesis 2 Induction of Ca oscillations Hepatocytes (rats) Ap3A, Ap4A [25] Priming of the respiratory burst of oxidase activity Human neutrophils Ap3A, Ap4A, probably non-speci¢c [26] ATP is more active Negative feedback for excitation Hippocampus Ap4A, Ap5A [27] Inhibition of sperm motility Human spermatozoa Ap3A, Ap4A [28] Decrease of coronary perfusion pressure Isolated rabbit hearts Ap3A, Ap4A [29] 2 Regulation of Ca release via ryanodine receptors Hepatocytes, skeletal muscle, cardiac Ap3A, Ap4A [30] muscle Glycogen phosphorylase activation Rat liver cells Ap3A, Ap4A [21] Vasoconstrictor and vasodilator actions Rat mesenteric arteries, isolated rat ApnA(n = 2^6) [31,32] perfused kidney Antitrombolytic e¡ect, antagonists of ADP-induced Human and rabbit platelets Ap4A and its non-hydrolysable [33] aggregation of human platelets analog 2 Increase in intracellular Ca Human neutrophils ApnA(n = 3^6) [19] Stimulation of gluconeogenesis Isolated rat proximal tubules Ap3A, Ap4A, ATP [34] Inhibition of adenosine kinase activity Rat liver ApnA [35] Control of timing of cell division E. coli Ap4A [36] Delay of apoptosis Neutrophils Ap5A, Ap6A [20] A tight relation between the metabolic state of cardiac nounced protection from apoptosis that was observed during muscle and the level of Ap5A was revealed [15]. Ischemia incubation with either Ap4A or the cytokine. ApnA-induced induced a 10-fold decrease in cardiac Ap5A levels where the e¡ects do not necessarily have the complex physiological na- major sensor of metabolic stress is the ATP-sensitive K ture; for example, rat liver glycogen phosphorylase is acti- channel [16] an opening of which promotes cellular survival vated by ApnA [21]. under ischemic injury. It is suggested that the nucleotide bind- By no means, this list of ApnA e¡ects is incomplete and will ing domains of KATP channelWprotein complex may serve as be extended tremendously in the coming years. But even the targets for Ap5A [15,17]. ApnA evoked inward and outward limited number of examples clearly demonstrates a high var- ionic current £ows by activating purinoreceptors in Xenopus iability of cell and tissue targets accompanied by a wide di- laevis follicular oocytes [18]. Inward currents were mediated versity of the induced e¡ects. The most probable assumption by a suramin-sensitive P2 receptor which showed at 10 WMof that uni¢es these highly diverse patterns is to consider ApnA ApnA the following agonist potency order: Ap4A s ATP s family as the signal transduction molecules. If this hypothesis Ap3A. Outward currents were mediated by a theophylline- suggested by several groups adequately re£ects present-state sensitive P1 receptor which possesses an agonist potency of understanding of ApnA role, then one should expect to ¢nd Ap2A s ATPEAp4A. Control experiments showed that there multiple factors that transmit their signals via changes in the was no breakdown of the ApnA to ATP, ADP, or AMP. All concentration of ApnA in response to their action. Table 2 ApnA tested so far (n from 2 to 6) stimulated an increase in shows that this prediction is supported by many observations. intracellular concentration of Ca2 in human neutrophils. Most remarkably, interferon causes entirely opposite e¡ects This increase was abolished if cells were pretreated with on the Ap4A and Ap3A levels, 10-fold decrease and 3^5- pertussis toxin known to interfere with activity of G proteins fold increase, respectively. Consequently, the Ap4A/Ap3A ra- [19]. tio is changed 30^50-fold. Interferons are well known to cause Neutrophyl apoptosis could be delayed by inoculating the an inhibition of cell proliferation. On the other hand, in pro- cells with ATP, Ap3A, or Ap4A [20]. Moreover, addition of liferating cells Ap4A increases tremendously, opposite to the these compounds together with a cytokine (granulocyte-mac- resting cells.
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