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BBA - Gene Regulatory Mechanisms (v.1799, #10-12)

Editorial Board (pp. i).

Cumulative Contents (pp. i-iv).

Editorial Board (pp. i).

Cumulative Contents (pp. i-iv).

Small molecule modulators of chromatin and coactivators by Tapas K. Kundu (pp. 669-670).

Chromatin remodeling regulation by small molecules and metabolites by Giosalba Burgio; Maria C. Onorati; Davide F.V. Corona (pp. 671-680).

The eukaryotic genome is a highly organized nucleoprotein structure comprising of DNA, histones, non-histone proteins, and RNAs, referred to as chromatin. The chromatin exists as a dynamic entity, shuttling between the open and closed forms at specific nuclear regions and loci based on the requirement of the cell. This dynamicity is essential for the various DNA-templated phenomena like transcription, replication, and repair and is achieved through the activity of ATP-dependent chromatin remodeling complexes and covalent modifiers of chromatin. A growing body of data indicates that chromatin enzymatic activities are finely and specifically regulated by a variety of small molecules derived from the intermediary metabolism. This review tries to summarize the work conducted in many laboratories and on different model organisms showing how ATP-dependent chromatin remodeling complexes are regulated by small molecules and metabolites such as adenosine triphosphate (ATP), acetyl coenzyme A (AcCoA), S-adenosyl methionine (SAM), nicotinamide adenine dinucleotide (NAD), and inositol polyphosphates (IPs).

Keywords: Chromatin remodeling; ATP; AcCoA; SAM; NAD; Poly-ADP-ribosylation; Phosphatidylinositide; Inositol polyphosphates

Chromatin remodeling regulation by small molecules and metabolites by Giosalba Burgio; Maria C. Onorati; Davide F.V. Corona (pp. 671-680).

Keywords: Chromatin remodeling; ATP; AcCoA; SAM; NAD; Poly-ADP-ribosylation; Phosphatidylinositide; Inositol polyphosphates

NAD: A master regulator of transcription by Sanchari Ghosh; Suji George; Upasana Roy; Deepti Ramachandran; Ullas Kolthur-Seetharam (pp. 681-693).

Cellular processes such as proliferation, differentiation and death are intrinsically dependent upon the redox status of a cell. Among other indicators of redox flux, cellular NAD(H) levels play a predominant role in transcriptional reprogramming. In addition to this, normal physiological functions of a cell are regulated in response to perturbations in NAD(H) levels (for example, due to alterations in diet/metabolism) to maintain homeostatic conditions. Cells achieve this homeostasis by reprogramming various components that include changes in chromatin structure and function (transcription). The interdependence of changes in gene expression and NAD(H) is evolutionarily conserved and is considered crucial for the survival of a species (by affecting reproductive capacity and longevity). Proteins that bind and/or use NAD(H) as a co-substrate (such as, CtBP and PARPs/Sirtuins respectively) are known to induce changes in chromatin structure and transcriptional profiles. In fact, their ability to sense perturbations in NAD(H) levels has been implicated in their roles in development, stress responses, metabolic homeostasis, reproduction and aging or age-related diseases. It is also becoming increasingly clear that both the levels/activities of these proteins and the availability of NAD(H) are equally important. Here we discuss the pivotal role of NAD(H) in controlling the functions of some of these proteins, the functional interplay between them and physiological implications during calorie restriction, energy homeostasis, circadian rhythm and aging.► NAD(H) is a key metabolite that links metabolic inputs to gene regulation. ► NAD(H) regulates transcription/chromatin structure through Sirts, PARPs and CtBP. ► NAD metabolites associate with and/or affect chromatin structure. ► NAD(H) is essential for maintaining normal organismal physiology.

Keywords: Abbreviations; NAD; Nicotinamide adenine dinucleotide; NAD(H); NAD; ⁺; and/or NADH; SIR; Silent information regulator; NAM; Nicotinamide; ADPR; ADP-ribose; OAADPR; O-acetyl-ADP-ribose; CR; Calorie restrictionNAD; Chromatin; Transcription; Histone; Sir2; Sirt1; Sirt6; Sirt7; CtBP; Redox; Homeostasis; Calorie restriction; Circadian rhythm; Aging; ADPR; OAADPR; Deacetylation; ADP-ribosylation; NPAS2

NAD: A master regulator of transcription by Sanchari Ghosh; Suji George; Upasana Roy; Deepti Ramachandran; Ullas Kolthur-Seetharam (pp. 681-693).

Interplay between microRNAs and the epigenetic machinery: An intricate network by Marilena V. Iorio; Claudia Piovan; Carlo M. Croce (pp. 694-701).

microRNAs take their place into the epigenetic world revealing a complicated network of reciprocal interconnections: not only they are able to control gene expression at a post-transcriptional level, thus representing a new important class of regulatory molecules, but they are also directly connected to the epigenetic machinery through a regulatory loop. Indeed, if epigenetic modifications, such as DNA methylation or histone acetylation, have been demonstrated to affect microRNA expression, and to be potentially responsible for the aberrant miRNA regulation observed in cancer, the other side of the coin is represented by the capacity of microRNAs to control the epigenetic machinery directly targeting its enzymatic components.This review will analyze and describe the regulatory loop interconnecting microRNAs and epigenetics, describing either how epigenetics can affect the miRNome, as well as how epi-miRNAs can control the epigenome, particularly focusing on the alterations observed in human cancer.

Keywords: microRNAs; Epigenetic regulation; Human cancer

Interplay between microRNAs and the epigenetic machinery: An intricate network by Marilena V. Iorio; Claudia Piovan; Carlo M. Croce (pp. 694-701).

Keywords: microRNAs; Epigenetic regulation; Human cancer

Protein lysine acetylation in cellular function and its role in cancer manifestation by Mohammed Arif; Parijat Senapati; Jayasha Shandilya; Tapas K. Kundu (pp. 702-716).

Lysine acetylation appears to be crucial for diverse biological phenomena, including all the DNA-templated processes, metabolism, cytoskeleton dynamics, cell signaling, and circadian rhythm. A growing number of cellular proteins have now been identified to be acetylated and constitute the complex cellular acetylome. Cross-talk among protein acetylation together with other post-translational modifications fine-tune the cellular functions of different protein machineries. Dysfunction of acetylation process is often associated with several diseases, especially cancer. This review focuses on the recent advances in the role of protein lysine acetylation in diverse cellular functions and its implications in cancer manifestation.► Acetylation at lysine residue regulates the function of many proteins. ► Acetylation thus plays a role in regulation of various biological processes. ► These biological processes are necessary for the normal functioning of cells. ► Altered acetylation-deacetylation dynamics leads to disease state such as cancer and thus could be potential target for therapeutics.

Keywords: Acetylation; Cancer; Acetyltransferases; Tumor suppressor

Protein lysine acetylation in cellular function and its role in cancer manifestation by Mohammed Arif; Parijat Senapati; Jayasha Shandilya; Tapas K. Kundu (pp. 702-716).

Keywords: Acetylation; Cancer; Acetyltransferases; Tumor suppressor

Histone deacetylase inhibitors: A chemical genetics approach to understanding cellular functions by Paul A. Marks (pp. 717-725).

There are eleven zinc dependent histone deacetylases (HDAC) in humans which have histones and many non-histone substrates. The substrates of these enzymes include proteins that have a role in regulation of gene expression, cell proliferation, cell migration, cell death, immune pathways and angiogenesis. Inhibitors of HDACs (HDACi) have been developed which alter the structure and function of these proteins, causing molecular and cellular changes that induce transformed cell death. The HDACi are being developed as anti-cancer drugs and have therapeutic potential for many non-oncologic diseases.

Keywords: Histone deacetylase; DNA double strand break; HDAC inhibitor; Mechanism of action; Apoptosis; Suberoylanilide hydroxamic acid

Histone deacetylase inhibitors: A chemical genetics approach to understanding cellular functions by Paul A. Marks (pp. 717-725).

Keywords: Histone deacetylase; DNA double strand break; HDAC inhibitor; Mechanism of action; Apoptosis; Suberoylanilide hydroxamic acid

Inhibitors to understand molecular mechanisms of NAD⁺-dependent deacetylases (sirtuins) by Michael Lawson; Urszula Uciechowska; Jörg Schemies; Tobias Rumpf; Manfred Jung; Wolfgang Sippl (pp. 726-739).

Histone deacetylases (HDACs) are enzymes that cleave acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Unlike the other three of the four classes of HDACs that have been identified in humans, which are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD⁺) for their catalytic activity. The seven members of the class III HDACs are also named sirtuins for their homology to Sir2p, a yeast histone deacetylase. Sirtuin inhibitors have been critical for the linkage of sirtuin activity to many physiological and pathological processes, and sirtuin activity has been associated with the pathogenesis of cancer, HIV, and metabolic and neurological diseases. Presented here is an overview of the many sirtuin inhibitors that have provided insight into the biological role of sirtuins.

Keywords: Histone deacetylases; Sirtuins; Inhibitor design

Sirtuin activators: Designing molecules to extend life span by Antoni Camins; Francesc X. Sureda; Felix Junyent; Ester Verdaguer; Jaume Folch; Carme Pelegri; Jordi Vilaplana; Carlos Beas-Zarate; Pallas Mercè Pallàs (pp. 740-749).

Resveratrol (RESV) exerts important pharmacological effects on human health: in addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it also modulates neuronal energy homeostasis and shows antiaging properties. Although it clearly has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of major interest concerns the effects of RESV on the activity of sirtuin 1 (SIRT1), an NAD⁺-dependent histone deacetylase that has been implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the antiaging properties of RESV, which increases life span in various organisms ranging from yeast to rodents. In addition, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidaemias or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, which are currently undergoing clinical trials, could be potential drugs for the treatment of type 2 diabetes, obesity, and metabolic syndrome, among other disorders. This review summarises current knowledge about the biological functions of SIRT1 in aging and aging-associated diseases and discusses its potential as a pharmacological target.

Keywords: Sirtuins; Resveratrol; Neurodegenerative diseases; Diabetes; Sirtuin activators

DNA methylation and demethylation probed by small molecules by Moshe Szyf (pp. 750-759).

DNA methylation is a covalent modification of DNA that plays an important role in setting gene expression programs during development. Recent evidence suggests that changes in DNA methylation patterns are involved in human disease through altering normal gene expression programming. In contrast to genetic changes aberrant DNA methylation patterns are potentially reversible raising the hope for DNA methylation based therapeutics. It was previously believed that the only relevant DNA methylation reaction in mature cells is DNA methyltransferase (DNMT), which accurately copies the DNA methylation pattern during cell division. The major effort in the field has therefore focused on developing DNMT inhibitors for cancer a disease of mitotic cells. However, recent evidence suggests that the DNA methylation state in both mitotic and postmitotic cells is a balance of DNA methylating and demethylating activities. This expands the scope of DNMT inhibitors to postmitotic tissues such as the brain. Since the identity of the DNA demethylating activity is still a mystery, the development of DNA demethylation inhibitors has been lagging. This review will discuss DNA methylation and demethylation machineries, and their therapeutic potentials as targets for small molecule inhibitors.►DNA methylation is a balance of methylation and demethylation activities. ►DNA methylation patterns are altered in disease. ►Cancer is distinguished by hypermethylation of certain genes and hypomethylation of other genes. ►DNA methylation inhibitors are used clinically as anticancer agents. ►DNA demethylation inhibitors are potential new therapeutics.

Keywords: DNA methylation; Small molecules; 5-azaC; Epigenetics; Anticancer drug; DNA demethylation; SAM; MBD2

DNA methylation and demethylation probed by small molecules by Moshe Szyf (pp. 750-759).

Keywords: DNA methylation; Small molecules; 5-azaC; Epigenetics; Anticancer drug; DNA demethylation; SAM; MBD2

Histone acetylation modulation by small molecules: A chemical approach by Margarete von Wantoch Rekowski; Athanassios Giannis (pp. 760-767).

Histone acetyltransferases (HATs) are enzymes able to acetylate lysine side chains of histones. They play essential roles in normal cell function as well as in pathogenesis of a broad set of diseases, including multiple cancers, HIV, diabetes mellitus, and neurodegenerative disorders. Moreover, several HATs are able to acetylate various non-histone protein substrates e.g. transcription factors, enzymes involved in glycolysis, fatty acid and glycogen metabolism, the tricarboxylic acid and urea cycles, suggesting that lysine acetylation represents an important regulatory mechanism similar to protein phosphorylation. Small molecule inhibitors of histone acetyltransferases have been developed in the last years and proved to be powerful tools to provide new insights into the mechanisms and the role of protein acetylation in gene regulation. This article highlights recent advances in the development of small molecule modulators of histone acetyltransferases.

Keywords: Histone acetyltransferases; Inhibitors

Histone acetylation modulation by small molecules: A chemical approach by Margarete von Wantoch Rekowski; Athanassios Giannis (pp. 760-767).

Keywords: Histone acetyltransferases; Inhibitors

Small-molecule regulators that mimic transcription factors by Rodriguez-Martinez José A. Rodríguez-Martínez; Kimberly J. Peterson-Kaufman; Aseem Z. Ansari (pp. 768-774).

Transcription factors (TFs) are responsible for decoding and expressing the information stored in the genome, which dictates cellular function. Creating artificial transcription factors (ATFs) that mimic endogenous TFs is a major goal at the interface of biology, chemistry, and molecular medicine. Such molecular tools will be essential for deciphering and manipulating transcriptional networks that lead to particular cellular states. In this minireview, the framework for the design of functional ATFs is presented and current challenges in the successful implementation of ATFs are discussed.►Components of natural transcription factors can be replaced with synthetic counterparts. ►ATFs will be essential tools for understanding and manipulating cellular states. ►ATF design requires the synergy of chemists, biologists, bioinformaticians, and bioengineers.

Keywords: Chemical biology; Synthetic biology; Transcription factor mimic; Gene regulation; Cooperative binding; Protein–DNA interaction

Small-molecule regulators that mimic transcription factors by Rodriguez-Martinez José A. Rodríguez-Martínez; Kimberly J. Peterson-Kaufman; Aseem Z. Ansari (pp. 768-774).

Keywords: Chemical biology; Synthetic biology; Transcription factor mimic; Gene regulation; Cooperative binding; Protein–DNA interaction

Inhibiting NF-κB activation by small molecules as a therapeutic strategy by Subash C. Gupta; Chitra Sundaram; Simone Reuter; Bharat B. Aggarwal (pp. 775-787).

Because nuclear factor-κB (NF-κB) is a ubiquitously expressed proinflammatory transcription factor that regulates the expression of over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation, the NF-κB signaling pathway has become a potential target for pharmacological intervention. A wide variety of agents can activate NF-κB through canonical and noncanonical pathways. Canonical pathway involves various steps including the phosphorylation, ubiquitination, and degradation of the inhibitor of NF-κB (IκBα), which leads to the nuclear translocation of the p50–p65 subunits of NF-κB followed by p65 phosphorylation, acetylation and methylation, DNA binding, and gene transcription. Thus, agents that can inhibit protein kinases, protein phosphatases, proteasomes, ubiquitination, acetylation, methylation, and DNA binding steps have been identified as NF-κB inhibitors. Because of the critical role of NF-κB in cancer and various chronic diseases, numerous inhibitors of NF-κB have been identified. In this review, however, we describe only small molecules that suppress NF-κB activation, and the mechanism by which they block this pathway.

Keywords: Abbreviations; AgR; antigen receptor; ATM; ataxia-telangiectasia mutant; BAFF; B-cell activating factor; BCL; B-cell lymphoma; BCR; B cell receptor; CARMA; CARD-containing MAGUK protein; CD40L; CD40 ligand; CK; casein kinase; DSBS; Doublestranded DNA breaks; ECSIT; evolutionary conserved signaling intermediates on Toll pathways; EGF; epidermal growth factor; EGFR; EGF receptor; ELKS; glutamate, leucine, lysine, serine-rich protein; GSK; glycogen synthase kinase; Hsp90; heat shock protein 90; IκB; inhibitor of NF-κB; IKK; IκB kinase; IRAK; IL-1R-associated kinase; LTβ; lymphotoxin β; LPS; lipopolysaccharide; MALT; mucosa-associated lymphoid tissue; MAPK; mitogen activated protein kinase; MAPK/Erk; kinase kinase; MyD88; myeloid differentiation factor; NF-κB; nuclear factor-κB; NIK; NF-κB-inducing kinase; NEMO; NF-κB essential modulator; PDK; Phosphoinositide-dependent kinase; PI3K; phosphatidylinositol 3-kinase; PKC; protein kinase C; PLC; phospholipase C; RANKL; receptor activator of NF-κB ligand; RIP; receptor-interacting protein; Syk; Spleen tyrosine kinase; TAB; TAK1-binding protein; TAK; transforming growth factor-β-activated kinase; TCR; T cell receptor; TLR; Toll-like receptor; TNF; tumour necrosis factor; TNFR1; TNF receptor 1; Tpl2; tumour progression locus-2; TRADD; TNF-receptor-associated death domain protein; TRAF; TNF-receptor-associated factorInflammation; NF-κB; Small molecule inhibitors; Therapeutics

Inhibiting NF-κB activation by small molecules as a therapeutic strategy by Subash C. Gupta; Chitra Sundaram; Simone Reuter; Bharat B. Aggarwal (pp. 775-787).

Small molecule regulators of Rb–E2F pathway as modulators of transcription by Sandeep Singh; Jackie Johnson; Srikumar Chellappan (pp. 788-794).

The retinoblastoma tumor suppressor protein, Rb, plays a major role in the regulation of mammalian cell cycle progression. It has been shown that Rb function is essential for the proper modulation of G1/S transition and inactivation of Rb contributes to deregulated cell proliferation. Rb exerts its cell cycle regulatory functions mainly by targeting the E2F family of transcription factors and Rb has been shown to physically interact with E2Fs 1, 2 and 3, repressing their transcriptional activity. Multiple genes involved in DNA synthesis and cell cycle progression are regulated by E2Fs, and Rb prevents their expression by inhibiting E2F activity, inducing growth arrest. It has been established that inactivation of Rb by phosphorylation, mutation, or by the interaction of viral oncoproteins leads to a release of the repression of E2F activity, facilitating cell cycle progression. Rb-mediated repression of E2F activity involves the recruitment of a variety of transcriptional co-repressors and chromatin remodeling proteins, including histone deacetylases, DNA methyltransferases and Brg1/Brm chromatin remodeling proteins. Inactivation of Rb by sequential phosphorylation events during cell cycle progression leads to a dissociation of these co-repressors from Rb, facilitating transcription. It has been found that small molecules that prevent the phosphorylation of Rb prevent the dissociation of certain co-repressors from Rb, especially Brg1, leading to the maintenance of Rb-mediated transcriptional repression and cell cycle arrest. Such small molecules have anti-cancer activities and will also act as valuable probes to study chromatin remodeling and transcriptional regulation.

Keywords: Raf-1; Cyclin dependent kinase; RRD-251; Cell cycle arrest; Transcriptional repression

Small molecule regulators of Rb–E2F pathway as modulators of transcription by Sandeep Singh; Jackie Johnson; Srikumar Chellappan (pp. 788-794).

Keywords: Raf-1; Cyclin dependent kinase; RRD-251; Cell cycle arrest; Transcriptional repression

Mechanism of interaction of small transcription inhibitors with DNA in the context of chromatin and telomere by Saptaparni Ghosh; Parijat Majumder; Suman Kalyan Pradhan; Dipak Dasgupta (pp. 795-809).

Small molecules from natural and synthetic sources have long been employed as human drugs. The transcription inhibitory potential of one class of these molecules has paved their use as anticancer drugs. The principal mode of action of these molecules is via reversible interaction with genomic DNA, double and multiple stranded. In this article we have revisited the mechanism of the interaction in the context of chromatin and telomere. The established modes of association of these molecules with double helical DNA provide a preliminary mechanism of their transcription inhibitory potential, but the scenario assumes a different dimension when the genomic DNA is associated with proteins in the transcription apparatus of both prokaryotic and eukaryotic organisms. We have discussed this altered scenario as a prelude to understand the chemical biology of their action in the cell. For the telomeric quadruplex DNA, we have reviewed the mechanism of their association with the quadruplex and resultant cellular consequence.

Keywords: Small transcription inhibitor; Chromatin; Telomere; Nucleoid; Intercalator; Groove binder

Small molecule modulators of histone acetylation and methylation: A disease perspective by B. Ruthrotha Selvi; D.V. Mohankrishna; Yogesh B. Ostwal; Tapas K. Kundu (pp. 810-828).

Chromatin modifications have gained immense significance in the past few decades as key regulators of gene expression. The enzymes responsible for these modifications along with the other non-histone proteins, remodeling factors and small RNAs modulate the chromatin dynamicity, which in turn directs the chromatin function. A concerted action of different modifying enzymes catalyzes these modifications, which are read by effector modules and converted to functional outcomes by various protein complexes. Several small molecules in the physiological system such as acetyl CoA, NAD⁺, and ATP are actively involved in regulating these functional outcomes. Recent understanding in the field of epigenetics indicate the possibility of the existence of a network, ‘the epigenetic language’ involving cross talk among different modifications that could regulate cellular processes like transcription, replication and repair. Hence, these modifications are essential for the cellular homeostasis, and any alteration in this balance leads to a pathophysiological condition or disease manifestation. Therefore, it is becoming more evident that modulators of these modifying enzymes could be an attractive therapeutic strategy, popularly referred to as ‘Epigenetic therapy.’ Although this field is currently monopolized by DNA methylation and histone deacetylase inhibitors, this review highlights the modulators of the other modifications namely histone acetylation, lysine methylation and arginine methylation and argues in favor of their therapeutic potential.► Histone modifications are important regulators of gene expression in both physiological and pathophysiological states. ► The histone modifications mainly acetylation, lysine methylation and arginine methylation together establish an epigenetic network. ► Histone acetylation aberrations have been reported in diseases such as cancer, diabetes, inflammatory disorders as well as neurodegenerative states. ► Acetylation inhibitors are showing great promise as potential therapeutic agents due to their anti-inflammatory, anti-cancer as well as anti-HIV properties. ► Since the epigenetic marks exist as a network, and there are evidences implicating their role in different diseases, potential therapeutic strategy should be towards combinatorial targeting of these modifications.

Keywords: Histone acetylation; Lysine methylation; Epigenetics; Arginine methylation; Inflammation; Modulator

Small molecule modulators of histone acetylation and methylation: A disease perspective by B. Ruthrotha Selvi; D.V. Mohankrishna; Yogesh B. Ostwal; Tapas K. Kundu (pp. 810-828).

Keywords: Histone acetylation; Lysine methylation; Epigenetics; Arginine methylation; Inflammation; Modulator

Aurora kinase inhibitors as anticancer molecules by Hiroshi Katayama; Subrata Sen (pp. 829-839).

Aurora kinase family of serine/threonine kinases are important regulators of mitosis that are frequently over expressed in human cancers and have been implicated in oncogenic transformation including development of chromosomal instability in cancer cells. In humans, among the three members of the kinase family, Aurora-A, -B and -C, only Aurora-A and -B are expressed at detectable levels in all somatic cells undergoing mitotic cell division and have been characterized in greater detail for their involvement in cellular pathways relevant to the development of cancer associated phenotypes. Aurora-A and -B are being investigated as potential targets for anticancer therapy. Development of inhibitors against Aurora kinases as anticancer molecules gained attention because of the facts that aberrant expression of these kinases leads to chromosomal instability and derangement of multiple tumor suppressor and oncoprotein regulated pathways. Preclinical studies and early phase I and II clinical trials of multiple Aurora kinase inhibitors as targeted anticancer drugs have provided encouraging results. This article discusses functional involvement of Aurora kinase-A and -B in the regulation of cancer relevant cellular phenotypes together with findings on some of the better characterized Aurora kinase inhibitors in modulating the functional interactions of Aurora kinases. Future possibilities about developing next generation Aurora kinase inhibitors and their clinical utility as anticancer therapeutic drugs are also discussed.► Aurora kinase family members are over expressed in many human cancers. ► Aurora kinase-A and -B have been implicated in tumorigenic transformation of cells. ► Aurora kinase inhibitors induce apoptosis of cancer cells and inhibition of tumor growth. ► Aurora kinase inhibitors are currently undergoing clinical trials for cancer therapy.

Keywords: Aurora kinase; Mitosis; Chromosomal instability; Aurora kinase inhibitor; Cancer therapy

Aurora kinase inhibitors as anticancer molecules by Hiroshi Katayama; Subrata Sen (pp. 829-839).

Keywords: Aurora kinase; Mitosis; Chromosomal instability; Aurora kinase inhibitor; Cancer therapy

Tuning acetylation levels with HAT activators: Therapeutic strategy in neurodegenerative diseases by B. Ruthrotha Selvi; Jean-Christophe Cassel; Tapas K. Kundu; Anne-Laurence Boutillier (pp. 840-853).

Neurodegenerative diseases, such as polyglutamine-related diseases, amyotrophic lateral sclerosis, and Alzheimer's disease are accompanied by transcriptional dysfunctions, leading to neuronal death. It is becoming more evident that the chromatin acetylation status is impaired during the lifetime of neurons, by a common mechanism related to the loss of function of histone acetyltransferase (HAT) activity. Notably, the HAT termed cAMP response element binding protein (CREB)–binding protein (CBP) was shown to display neuroprotective functions. Several other HATs have now been shown to participate in basic but vital neuronal functions. In addition, there is increasing evidence of several HATs (including CBP), as essential regulators of neuronal plasticity and memory formation processes. In order to counteract neuronal loss and/or memory deficits in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules antagonizing histone deacetylase (HDAC) activity (i.e. HDAC inhibitors). Although this strategy lacks specificity, some of these molecules display promising therapeutic properties. With the rapidly evolving literature on HATs and their respective functions in neuronal survival and memory formation, it seems essential to envisage direct stimulation of the acetyltransferase function as a new therapeutic tool in neurodegenerative diseases. In this review, we will highlight the present understanding and the future prospects of such therapeutic approach.► HATs are essential regulators of neuronal plasticity and memory formation processes. ► Down-regulation of histone acetylation is associated with neurodegeneration and memory loss. ► HDAC inhibition strategies present therapeutic benefits but lack specificity. ► Targeting HAT activation may more accurately restore a specific chromatin marking. ► HAT activator molecules represent promising tools against neurodegenerative diseases.

Keywords: Neurodegenerative disease; Memory; Histone acetyltransferase; Acetylation; Neuronal death; CREB-binding protein

Small molecules from natural sources, targeting signaling pathways in diabetes by Qiong Liu; Lili Chen; Lihong Hu; Yuewei Guo; Xu Shen (pp. 854-865).

Diabetes mellitus (DM) is a metabolic disease caused by genetic or environmental factors. It has rendered a severe menace to the middle-aged and elderly, while there is still lack of efficient drugs against this disease. The pathogenic mechanism for DM is complex, and the complicated networks related to this disease involve distinct signaling pathways. Currently, discovery of potential modulators targeting these pathways has become a potent approach for anti-diabetic drug lead compound development. Compared with synthetic compounds, natural products provide inherent larger-scale structural diversity and have been the major resource of bioactive agents for new drug discovery. To date, more and more active components from plants or marine organisms have been reported to regulate diabetic pathophysiological signaling pathways and exhibit anti-diabetic activity. This review will summarize the regulation of natural small molecules on some key signaling pathways involved in DM. These pathways include insulin signaling pathway, carbohydrate metabolism pathway, the pathways involving insulin secretion and PPAR regulation, endoplasmic reticulum (ER) stress and inflammation related pathways and chromatin modification pathways.

Keywords: Natural product; Diabetes; Insulin; AMP-activated protein kinase; Endoplasmic reticulum stress

Small molecules from natural sources, targeting signaling pathways in diabetes by Qiong Liu; Lili Chen; Lihong Hu; Yuewei Guo; Xu Shen (pp. 854-865).

Keywords: Natural product; Diabetes; Insulin; AMP-activated protein kinase; Endoplasmic reticulum stress

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BBA - Gene Regulatory Mechanisms (v.1799, #10-12)