МикроРНК: половые гормоны, гормональный канцерогенез, гормоночувствительность опухолевой ткани

Sex hormones, regulating normal physiological processes of most tissues and organs, are considered to be one of the key factors in the development and progression of the reproductive system cancer. Recently, the importance of the system for post-transcriptional control of gene expression mediated by short single-stranded RNA molecules (microRNA) became evident. This system is involved in regulation of normal physiological processes and in the pathogenesis of many diseases, including cancer. In review we discuss the relationship between the two regulatory systems – sex hormones and microRNAs. The relationship of these systems is considered in the context of two tumors – breast and prostate cancer. In particular, the history of research on the role of sex hormones in the pathogenesis of breast cancer and prostate cancer is briefly covered. Additionally, modern scientific data on the biogenesis and biological role of microRNAs are presented in more detail. In the cells of the hormone-sensitive tissues, sex hormones regulate the microRNA-mediated machinery of gene expression control by two known ways: specifically, affecting the activity of individual microRNA molecules and non-specifically by altering the efficiency of microRNA biogenesis and activity of RNA-induced silencing complex. This downstream regulatory network substantially enhances biological effects of sex hormones at physiological conditions. Malignant transformation leads to a distortion of the regulatory effects of sex hormones that crucially influence the system of microRNA-regulated post-transcriptional control of gene expression. The most established and clinically significant example of such phenomenon is the loss of sensitivity of cells to the regulatory action of these hormones. As a consequence, cancer cells acquire the ability to active proliferation without stimulation with sex hormones. This effect is partly mediated by microRNAs. Also, relevant experimental data indicating the involvement of microRNAs in the phenomenon of breast cancer and prostate cancer cells hormone resistance are discussed in the review.Conception of the possible primary role of microRNAs in the process of malignant transformation and distortion of hormonal regulation is based on a smaller number of scientific reports. In general, in accordance with the main biological role of microRNAs, latter may affect sex hormones function via interaction with the mRNAs of hormone receptors and inhibition of their synthesis. As a result, the effect of many microRNA is converging on the single mRNA, results in suppression of corresponding protein function and, in the end, leads to inhibition of regulatory cascade downstream of sex steroids.Finally, the analysis of the fundamental aspects of sex hormones – microRNA interplay is supplemented by brief overview of clinically significant problems. The prospects for development and introduction into clinical practice innovative methods of diagnosis, prediction and optimization of therapy of breast and prostate cancers are discussed as well.Половые гормоны, регулируя нормальные физиологические процессы большинства тканей и органов, традиционно считаются одним из ключевых факторов развития и прогрессии опухолей органов репродуктивной системы. В течение последних лет стала очевидной значимость системы посттранскрипционного контроля генной экспрессии, опосредуемой короткими одноцепочечными молекулами РНК, так называемыми микроРНК, в регуляции нормальных физиологических процессов и в патогенезе многих заболеваний, включая онкологические. В представленном обзоре обсуждается взаимосвязь между двумя в определенном смысле самостоятельными регуляторными системами – половыми гормонами и микроРНК. Взаимоотношения этих систем рассматриваются в контексте двух онкологических заболеваний – рака молочной железы (РМЖ) и рака предстательной железы (РПЖ).Кратко освещается история исследований роли половых гормонов в патогенезе РМЖ и РПЖ, более подробно представлены современные данные о биогенезе и биологической роли микроРНК. В клетках гормоночувствительных тканей половые гормоны регулируют работу микроРНК-аппарата регуляции генной экспрессии двумя известными путями: специфично, влияя на активность отдельных молекул микроРНК, и неспецифично, изменяя эффективность биогенеза микроРНК и активность цитоплазматического РНК-белкового комплекса. С учетом работы такой регуляторной сети существенно расширяются представления о биологических эффектах половых гормонов в физиологических условиях. Злокачественная трансформация приводит к искажению регуляторных эффектов половых гормонов, что отражается и усиливается регулируемой ими системой посттранскрипционного контроля генной экспрессии, опосредуемой микроРНК. К числу наиболее исследованных и клинически значимых примеров этого феномена относится утрата чувствительности к влиянию половых гормонов, на фоне чего клетки приобретают способность к активной пролиферации безгормональной стимуляции за счет подключения коллатеральных сигнальных путей и ростовых факторов. Этот феномен отчасти опосредуется микроРНК, и как следствие, к обсуждению привлекаются современные экспериментальные данные, указывающие на причастность микроРНК к формированию феномена гормональной резистентности клеток РМЖ и РПЖ. Представления о возможной первичной роли нарушений функций микроРНК в процессе опухолевой трансформации и искажения механизмов гормональной регуляции основаны на меньшем количестве проведенных и опубликованных исследований. В целом, в соответствии с основной биологической ролью микроРНК, их таргетное воздействие на функции половых гормонов в основном опосредуется взаимодействием с различными участками матричной РНК (мРНК) соответствующих гормональных рецепторов и ведет к угнетению синтеза последних. В итоге действие многих микроРНК конвергируется на одной молекуле мРНК, что в большинстве случаев приводит к подавлению сигнальных каскадов, индуцируемых половыми гормонами.Анализ фундаментальных аспектов дополнен обзором клинически значимых проблем, в решении которых должна учитываться взаимосвязь половых гормонов и микроРНК. Коротко обсуждаются перспективы развития и внедрения в клиническую практику методов диагностики, прогнозирования и оптимизации терапии опухолевых заболеваний гормоночувствительных тканей на основе сведений о микроРНК и их связях с обсуждаемыми проблемами

Parafermionic Liouville field theory and instantons on ALE spaces

In this paper we study the correspondence between the $\hat{\textrm{su}}(n)_{k}\oplus \hat{\textrm{su}}(n)_{p}/\hat{\textrm{su}}(n)_{k+p}$ coset conformal field theories and $\mathcal{N}=2$ SU(n) gauge theories on $\mathbb{R}^{4}/\mathbb{Z}_{p}$. Namely we check the correspondence between the SU(2) Nekrasov partition function on $\mathbb{R}^{4}/\mathbb{Z}_{4}$ and the conformal blocks of the $S_{3}$ parafermion algebra (in $S$ and $D$ modules). We find that they are equal up to the U(1)-factor as it was in all cases of AGT-like relations. Studying the structure of the instanton partition function on $\mathbb{R}^4/\mathbb{Z}_p$ we also find some evidence that this correspondence with arbitrary $p$ takes place up to the U(1)-factor.Comment: 21 pages, 6 figures, misprints corrected, references added, version to appear in JHE

Instanton moduli spaces and bases in coset conformal field theory

Recently proposed relation between conformal field theories in two dimensions and supersymmetric gauge theories in four dimensions predicts the existence of the distinguished basis in the space of local fields in CFT. This basis has a number of remarkable properties, one of them is the complete factorization of the coefficients of the operator product expansion. We consider a particular case of the U(r) gauge theory on C^2/Z_p which corresponds to a certain coset conformal field theory and describe the properties of this basis. We argue that in the case p=2, r=2 there exist different bases. We give an explicit construction of one of them. For another basis we propose the formula for matrix elements.Comment: 31 pages, 3 figure

Classical Conformal Blocks and Accessory Parameters from Isomonodromic Deformations

Classical conformal blocks naturally appear in the large central charge limit of 2D Virasoro conformal blocks. In the $AdS_{3}/CFT_{2}$ correspondence, they are related to classical bulk actions and are used to calculate entanglement entropy and geodesic lengths. In this work, we discuss the identification of classical conformal blocks and the Painlev\'e VI action showing how isomonodromic deformations naturally appear in this context. We recover the accessory parameter expansion of Heun's equation from the isomonodromic $\tau$-function. We also discuss how the $c = 1$ expansion of the $\tau$-function leads to a novel approach to calculate the 4-point classical conformal block.Comment: 32+10 pages, 2 figures; v3: upgraded notation, discussion on moduli space and monodromies, numerical and analytic checks; v2: added refs, fixed emai

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

Challenges of beta-deformation

A brief review of problems, arising in the study of the beta-deformation, also known as "refinement", which appears as a central difficult element in a number of related modern subjects: beta \neq 1 is responsible for deviation from free fermions in 2d conformal theories, from symmetric omega-backgrounds with epsilon_2 = - epsilon_1 in instanton sums in 4d SYM theories, from eigenvalue matrix models to beta-ensembles, from HOMFLY to super-polynomials in Chern-Simons theory, from quantum groups to elliptic and hyperbolic algebras etc. The main attention is paid to the context of AGT relation and its possible generalizations.Comment: 20 page

Initial Mutations Direct Alternative Pathways of Protein Evolution

Whether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can constrain the type and order of selected mutations, but it can also make adaptive trajectories contingent upon the first random substitution. This effect is particularly strong under sign epistasis, when the sign of the fitness effects of a mutation depends on its genetic background. In the current study, we examine how epistatic interactions between mutations determine alternative evolutionary pathways, using in vitro evolution of the antibiotic resistance enzyme TEM-1 β-lactamase. First, we describe the diversity of adaptive pathways among replicate lines during evolution for resistance to a novel antibiotic (cefotaxime). Consistent with the prediction of epistatic constraints, most lines increased resistance by acquiring three mutations in a fixed order. However, a few lines deviated from this pattern. Next, to test whether negative interactions between alternative initial substitutions drive this divergence, alleles containing initial substitutions from the deviating lines were evolved under identical conditions. Indeed, these alternative initial substitutions consistently led to lower adaptive peaks, involving more and other substitutions than those observed in the common pathway. We found that a combination of decreased enzymatic activity and lower folding cooperativity underlies negative sign epistasis in the clash between key mutations in the common and deviating lines (Gly238Ser and Arg164Ser, respectively). Our results demonstrate that epistasis contributes to contingency in protein evolution by amplifying the selective consequences of random mutations

Mechanisms for the Evolution of a Derived Function in the Ancestral Glucocorticoid Receptor

Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs—reduced sensitivity to all hormones and increased selectivity for glucocorticoids—are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR–MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution

Instantons and 2d Superconformal field theory

A recently proposed correspondence between 4-dimensional N=2 SUSY SU(k) gauge theories on R^4/Z_m and SU(k) Toda-like theories with Z_m parafermionic symmetry is used to construct four-point N=1 super Liouville conformal block, which corresponds to the particular case k=m=2. The construction is based on the conjectural relation between moduli spaces of SU(2) instantons on R^4/Z_2 and algebras like \hat{gl}(2)_2\times NSR. This conjecture is confirmed by checking the coincidence of number of fixed points on such instanton moduli space with given instanton number N and dimension of subspace degree N in the representation of such algebra.Comment: 13 pages, exposition improved, references adde

Exact results for N = 2 supersymmetric gauge theories on compact toric manifolds and equivariant Donaldson invariants

We provide a contour integral formula for the exact partition function of N = 2 supersymmetric U(N) gauge theories on compact toric four-manifolds by means of supersymmetric localisation. We perform the explicit evaluation of the contour integral for U(2) N = 2 17 theory on CP2 for all instanton numbers. In the zero mass case, corresponding to the N = 4 supersymmetric gauge theory, we obtain the generating function of the Euler characteristics of instanton moduli spaces in terms of mock-modular forms. In the decoupling limit of infinite mass we find that the generating function of local and surface observables computes equivariant Donaldson invariants, thus proving in this case a longstanding conjecture by N. Nekrasov. In the case of vanishing first Chern class the resulting equivariant Donaldson polynomials are new. \ua9 2016, The Author(s)