Friday, August 19, 2016

MicroRNAs Used in Combination with Anti-Cancer Treatments Can Enhance Therapy Efficacy

Author(s):

Maddalena Mognato and Lucia CelottiPages 1052-1062 (11)

Abstract:


MicroRNAs (miRNAs), a recently discovered class of small non-coding RNAs, constitute a promising approach to anti-cancer treatments when they are used in combination with other agents. MiRNAs are evolutionarily conserved non-coding RNAs that negatively regulate gene expression by binding to the complementary sequence in the 3’-untranslated region (UTR) of target genes. MiRNAs typically suppress gene expression by direct association with target transcripts, thus decreasing the expression levels of target proteins. The delivery to cells of synthetic miRNAs that mimic endogenous miRNA targeting genes involved in the DNA-Damage Response (DDR) can perturb the process, making cells more sensitive to chemotherapy or radiotherapy. This review examines how cells respond to combined therapy and it provides insights into the role of miRNAs in targeting the DDR repair pathway when they are used in combination with chemical compounds or ionizing radiation to enhance cellular sensitivity to treatments.

Keywords:

Apoptosis, Cell cycle checkpoints, DNA-Damage Response, DNA Repair, microRNAs, Tumor resistance.

Affiliation:

Department of Biology, School of Science, University of Padova, Padova, Italy.


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G4 Aptamers: Trends in Structural Design

Author(s):

Anna Varizhuk, Nikolay Ilyinsky, Igor Smirnov and Galina PozmogovaPages 1-9 (9)

Abstract:


Many potent DNA aptamers are known to contain a G-quadruplex (G4) core. Structures and applications of the majority of such aptamers have been reviewed previously. The present review focuses on the design and optimization of G4 aptamers. General features of bioactive G4s are analyzed, and the main strategies for construction of aptamers with desired properties and topologies, including modular assembly, control of an aptamer folding and some others, are outlined. Chemical modification as a method for post-SELEX G4 aptamer optimization is also discussed, and the effects of loop and core modifications are compared. Particular attention is paid to the emerging trends, such as the development of genomic G4-inspired aptamers and the combinatorial approaches which aim to find a balance between rational design and selection.

Keywords:

aptamers; chemical modification; combinatorial approaches; drug design; G-quadruplexes; structure-activity relationship

Affiliation:

Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of FMBA, P.O. Box: 119435, Moscow, Russia


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Augmentation of Creatine in the Heart

Author(s):

Sevasti Zervou, Hannah J. Whittington, Angela J. Russell and Craig A. LygatePages 19-28 (10)

Abstract:


Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

Keywords:

Creatine transporter, energetics, heart disease.

Affiliation:

Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington OX3 7BN, UK.


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RAS/Effector Interactions from Structural and Biophysical Perspective

Author(s):

Ariel Erijman and Julia M. ShifmanPages 370-375 (6)

Abstract:


RAS is a molecular switch that regulates a large number of pathways through interactions with many effector proteins. Most RAS/effector complexes are short-lived, demonstrating fast association and fast dissociation rate and Kds ranging from 10-8–10-5 M, compatible with the signaling function of these interactions in the cell. RAS effectors share little sequence homology but all contain an RAS binding domain that exhibits ubiquitin fold. All effectors bind to the same epitope on RAS by forming an intermolecular beta sheet and creating a number of favorable hydrogen bonds and salt bridges across the binding interface. Several hot-spots on both RAS and effector molecules constitute a general recognition mode. RAS/effector interactions occur only when RAS is found in the active, GTP-bound state, and are disrupted upon GTP hydrolysis, most probably due to increased flexibility of the RAS molecule. Recent NMR studies demonstrate how in the presence of multiple binding partners, RAS prefers certain effectors to others. The hierarchy of these interactions could be altered for RAS oncogenic mutants, thus perturbing the network of the downstream signaling. Insights obtained through biophysical and structural studies of effectors interacting with RAS and its mutants establish the basic principles that could be used for designing drugs in RAS-associated diseases.

Keywords:

Binding affinity, complex structure, intermolecular interactions, protein-protein interactions.

Affiliation:

Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.


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Ras Dimer Formation as a New Signaling Mechanism and Potential Cancer Therapeutic Target

Author(s):

Mo Chen, Alec Peters, Tao Huang and Xiaolin NanPages 391-403 (13)

Abstract:


The K-, N-, and HRas small GTPases are key regulators of cell physiology and are frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive Ras based on known mechanisms of Ras signaling have been met with little success. Several studies have provided compelling evidence for the existence and biological relevance of Ras dimers, establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane. We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this model in both basic and translational Ras biology.

Keywords:

Ras signaling, Ras dimer, membrane clustering, cancer, targeted therapy.

Affiliation:

Department of Biomedical Engineering, Knight Cancer Institute, and OHSU Center for Spatial Systems Biomedicine (OCSSB), Oregon Health and Science University, Portland, OR.


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