scholarly journals Divergent regulation of the key enzymes of polyamine metabolism by chiral α-methylated polyamine analogues

2009 ◽  
Vol 422 (2) ◽  
pp. 321-328 ◽  
Author(s):  
Mervi T. Hyvönen ◽  
Michael T. Howard ◽  
Christine B. Anderson ◽  
Nikolay Grigorenko ◽  
Alex R. Khomutov ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Upstream Open Reading Frame ◽  
Polyamine Metabolism ◽  
Therapeutic Drug ◽  
Optical Isomers ◽  
Control Mechanisms ◽  
Reading Frame ◽  
Polyamine Analogues ◽  
Novel Approach ◽  
Polyamine Uptake

The natural polyamines are ubiquitous multifunctional organic cations which play important roles in regulating cellular proliferation and survival. Here we present a novel approach to investigating polyamine functions by using optical isomers of MeSpd (α-methylspermidine) and Me2Spm (α,ω-bismethylspermine), metabolically stable functional mimetics of natural polyamines. We studied the ability of MeSpd and Me2Spm to alter the normal polyamine regulation pathways at the level of polyamine uptake and the major control mechanisms known to affect the key polyamine metabolic enzymes. These include: (i) ODC (ornithine decarboxylase), which catalyses the rate-limiting step of polyamine synthesis; (ii) ODC antizyme, an inhibitor of ODC and polyamine uptake; (iii) SSAT (spermidine/spermine N1-acetyltransferase), the major polyamine catabolic enzyme; and (iv) AdoMetDC (S-adenosyl-L-methionine decarboxylase), which is required for the conversion of putrescine into spermidine, and spermidine into spermine. We show that the stereoisomers differ in their cellular uptake and ability to downregulate ODC and AdoMetDC, and to induce SSAT. These effects are mediated by the ability of the enantiomers to induce +1 ribosomal frameshifting on ODC antizyme mRNA, to suppress the translation of AdoMetDC uORF (upstream open reading frame) and to regulate the alternative splicing of SSAT pre-mRNA. The unique effects of chiral polyamine analogues on polyamine metabolism may offer novel possibilities for studying the physiological functions, control mechanisms, and targets of the natural polyamines, as well as advance therapeutic drug development in cancer and other human health-related issues.

scholarly journals A UV-Induced Mutation in Neurospora That Affects Translational Regulation in Response to Arginine

Genetics ◽  
1996 ◽  
Vol 142 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Michael Freitag ◽  
Nelima Dighde ◽  
Matthew S Sachs
Keyword(s):  
Translational Control ◽  
Translational Regulation ◽  
Fusion Gene ◽  
Mrna Translation ◽  
Small Subunit ◽  
Upstream Open Reading Frame ◽  
Control Mechanisms ◽  
Carbamoyl Phosphate ◽  
Altered Expression ◽  
Reading Frame

The Neurospora crmsu arg-2 gene encodes the small subunit of arginine-specific carbamoyl phosphate synthetase. The levels of arg-2 mRNA and mRNA translation are negatively regulated by arginine. An upstream open reading frame (uORF) in the transcript’s 5′ region has been implicated in arginine-specific control. An arg-2-hph fusion gene encoding hygromycin phosphotransferase conferred arginine-regulated resistance to hygromycin when introduced into N. crassa. We used an arg-2-hph strain to select for UV-induced mutants that grew in the presence of hygromycin and arginine, and we isolated 46 mutants that had either of two phenotypes. One phenotype indicated altered expression of both arg-2-hph and urg-2 genes; the other, altered expression of urg-2-hph but not arg-2. One of the latter mutations, which was genetically closely linked to arg-2-hph, was recovered from the 5′ region of the arg-2-hph gene using PCR. Sequence analyses and transformation experiments revealed a mutation at uORF codon 12 (Asp to Asn) that abrogated negative regulation. Examination of the distribution of ribosomes on arg-2-hph transcripts showed that loss of regulation had a translational component, indicating the uORF sequence was important for Arg-specific translational control. Comparisons with other uORFS suggest common elements in translational control mechanisms.

Polyamine metabolism in the Microsporidia

2003 ◽  
Vol 31 (2) ◽  
pp. 420-423 ◽  
Author(s):  
C.J. Bacchi ◽  
N. Yarlett ◽  
L.M. Weiss
Keyword(s):  
Metabolic Pathways ◽  
Tumour Cells ◽  
Polyamine Metabolism ◽  
Immunocompromised Patients ◽  
Obligate Intracellular ◽  
Polyamine Analogues ◽  
Intracellular Parasites ◽  
Recent Developments ◽  
Polyamine Uptake ◽  
Block Growth

Members of the phylum Microspora are all obligate intracellular parasites. Little is known concerning metabolic pathways in these parasites, some of which pose serious problems in immunocompromised patients. We investigated polyamine metabolism in the systemic pathogen Enterocytozoon cuniculi using intact pre-emergent spores, and cell-free preparations. We found both polyamine synthetic and interconversion pathways to be operative, as evidenced by conversion of ornithine into polyamines, and production of spermidine from spermine by pre-emergent spores. Recent developments in the antitumour field have highlighted the ability of bis-ethylated polyamine analogues to reduce polyamine levels and block growth of tumour cells. In light of enhanced polyamine uptake in Enc. cuniculi, we have begun to study bis-aryl 3-7-3 and bis-ethyl oligoamine analogues as leads for chemotherapy of microsporidia.

scholarly journals Polyamine analogues targeting epigenetic gene regulation

2009 ◽  
Vol 46 ◽  
pp. 95-110 ◽  
Author(s):  
Yi Huang ◽  
Laurence J. Marton ◽  
Patrick M. Woster ◽  
Robert A. Casero
Keyword(s):  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Significant Inhibition ◽  
Chromatin Remodelling ◽  
Polyamine Metabolism ◽  
Lysine Methylation ◽  
Protein Activity ◽  
Histone Lysine Methylation ◽  
Polyamine Analogues ◽  
Novel Approach

Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy.

scholarly journals Sucrose Control of Translation Mediated by an Upstream Open Reading Frame-Encoded Peptide

2009 ◽  
Vol 150 (3) ◽  
pp. 1356-1367 ◽  
Author(s):  
Fatemeh Rahmani ◽  
Maureen Hummel ◽  
Jolanda Schuurmans ◽  
Anika Wiese-Klinkenberg ◽  
Sjef Smeekens ◽  
...  
Keyword(s):  
Open Reading Frame ◽  
Upstream Open Reading Frame ◽  
Reading Frame

scholarly journals Translational regulation of Arabidopsis XIPOTL1 is modulated by phosphocholine levels via the phylogenetically conserved upstream open reading frame 30

2012 ◽  
Vol 63 (14) ◽  
pp. 5203-5221 ◽  
Author(s):  
Fulgencio Alatorre-Cobos ◽  
Alfredo Cruz-Ramírez ◽  
Celine A. Hayden ◽  
Claudia-Anahí Pérez-Torres ◽  
Anne-Laure Chauvin ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Open Reading Frame ◽  
Upstream Open Reading Frame ◽  
Reading Frame

scholarly journals Automated analysis of filopodial length and spatially resolved protein concentration via adaptive shape tracking

2016 ◽  
Vol 27 (22) ◽  
pp. 3616-3626 ◽  
Author(s):  
Tanumoy Saha ◽  
Isabel Rathmann ◽  
Abhiyan Viplav ◽  
Sadhana Panzade ◽  
Isabell Begemann ◽  
...  
Keyword(s):  
Protein Concentration ◽  
Growth Dynamics ◽  
Automated Analysis ◽  
Cell Types ◽  
Control Mechanisms ◽  
Spatially Resolved ◽  
Novel Approach ◽  
Associated Proteins

Filopodia are dynamic, actin-rich structures that transiently form on a variety of cell types. To understand the underlying control mechanisms requires precise monitoring of localization and concentration of individual regulatory and structural proteins as filopodia elongate and subsequently retract. Although several methods exist that analyze changes in filopodial shape, a software solution to reliably correlate growth dynamics with spatially resolved protein concentration along the filopodium independent of bending, lateral shift, or tilting is missing. Here we introduce a novel approach based on the convex-hull algorithm for parallel analysis of growth dynamics and relative spatiotemporal protein concentration along flexible filopodial protrusions. Detailed in silico tests using various geometries confirm that our technique accurately tracks growth dynamics and relative protein concentration along the filopodial length for a broad range of signal distributions. To validate our technique in living cells, we measure filopodial dynamics and quantify spatiotemporal localization of filopodia-associated proteins during the filopodial extension–retraction cycle in a variety of cell types in vitro and in vivo. Together these results show that the technique is suitable for simultaneous analysis of growth dynamics and spatiotemporal protein enrichment along filopodia. To allow readily application by other laboratories, we share source code and instructions for software handling.

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

2007 ◽  
Vol 35 (2) ◽  
pp. 318-321 ◽  
Author(s):  
J.L.A. Mitchell ◽  
T.K. Thane ◽  
J.M. Sequeira ◽  
R. Thokala
Keyword(s):  
Regulatory Protein ◽  
Feedback System ◽  
Uptake System ◽  
Polyamine Synthesis ◽  
Polyamine Analogues ◽  
Binding Partners ◽  
Polyamine Transport ◽  
Polyamine Uptake ◽  
Tumour Cell Growth

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

scholarly journals Cyber-physical networking for wireless mesh infrastructures

2012 ◽  
Vol 10 ◽  
pp. 113-118
Author(s):  
C. Mannweiler ◽  
C. Lottermann ◽  
A. Klein ◽  
J. Schneider ◽  
H. D. Schotten
Keyword(s):  
Network Control ◽  
Third Party ◽  
Mesh Network ◽  
Control Mechanisms ◽  
Autonomous Operation ◽  
Delay Jitter ◽  
Wireless Mesh ◽  
Novel Approach ◽  
Inference Systems ◽  
Management Functions

Abstract. This paper presents a novel approach for cyber-physical network control. "Cyber-physical" refers to the inclusion of different parameters and information sources, ranging from physical sensors (e.g. energy, temperature, light) to conventional network information (bandwidth, delay, jitter, etc.) to logical data providers (inference systems, user profiles, spectrum usage databases). For a consistent processing, collected data is represented in a uniform way, analyzed, and provided to dedicated network management functions and network services, both internally and, through an according API, to third party services. Specifically, in this work, we outline the design of sophisticated energy management functionalities for a hybrid wireless mesh network (WLAN for both backhaul traffic and access, GSM for access only), disposing of autonomous energy supply, in this case solar power. Energy consumption is optimized under the presumption of fluctuating power availability and considerable storage constraints, thus influencing, among others, handover and routing decisions. Moreover, advanced situation-aware auto-configuration and self-adaptation mechanisms are introduced for an autonomous operation of the network. The overall objective is to deploy a robust wireless access and backbone infrastructure with minimal operational cost and effective, cyber-physical control mechanisms, especially dedicated for rural or developing regions.

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