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Epigenetic changes in the estrogen receptor α gene promoter: implications in sociosexual behaviors  [PDF]
Ken Ichi Matsuda
Frontiers in Neuroscience , 2014, DOI: 10.3389/fnins.2014.00344
Abstract: Estrogen action through estrogen receptor α (ERα) is involved in the control of sexual and social behaviors in adult mammals. Alteration of ERα gene activity mediated by epigenetic mechanisms, such as histone modifications and DNA methylation, in particular brain areas appears to be crucial for determining the extents of these behaviors between the sexes and among individuals within the same sex. This review provides a summary of the epigenetic changes in the ERα gene promoter that correlate with sociosexual behaviors.
Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience  [PDF]
Robert Kumsta,Elisabeth Hummel,Frances S. Chen,Markus Heinrichs
Frontiers in Neuroscience , 2013, DOI: 10.3389/fnins.2013.00083
Abstract: Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene (OXTR) promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.
Differential Regulation of Smad3 and of the Type II Transforming Growth Factor-β Receptor in Mitosis: Implications for Signaling  [PDF]
Tal Hirschhorn, Lior Barizilay, Nechama I. Smorodinsky, Marcelo Ehrlich
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043459
Abstract: The response to transforming growth factor-β (TGF-β) depends on cellular context. This context is changed in mitosis through selective inhibition of vesicle trafficking, reduction in cell volume and the activation of mitotic kinases. We hypothesized that these alterations in cell context may induce a differential regulation of Smads and TGF-β receptors. We tested this hypothesis in mesenchymal-like ovarian cancer cells, arrested (or not) in mitosis with 2-methoxyestradiol (2ME2). In mitosis, without TGF-β stimulation, Smad3 was phosphorylated at the C-terminus and linker regions and localized to the mitotic spindle. Phosphorylated Smad3 interacted with the negative regulators of Smad signaling, Smurf2 and Ski, and failed to induce a transcriptional response. Moreover, in cells arrested in mitosis, Smad3 levels were progressively reduced. These phosphorylations and reduction in the levels of Smad3 depended on ERK activation and Mps1 kinase activity, and were abrogated by increasing the volume of cells arrested in mitosis with hypotonic medium. Furthermore, an Mps1-dependent phosphorylation of GFP-Smad3 was also observed upon its over-expression in interphase cells, suggesting a mechanism of negative regulation which counters increases in Smad3 concentration. Arrest in mitosis also induced a block in the clathrin-mediated endocytosis of the type II TGF-β receptor (TβRII). Moreover, following the stimulation of mitotic cells with TGF-β, the proteasome-mediated attenuation of TGF-β receptor activity, the degradation and clearance of TβRII from the plasma membrane, and the clearance of the TGF-β ligand from the medium were compromised, and the C-terminus phosphorylation of Smad3 was prolonged. We propose that the reduction in Smad3 levels, its linker phosphorylation, and its association with negative regulators (observed in mitosis prior to ligand stimulation) represent a signal attenuating mechanism. This mechanism is balanced by the retention of active TGF-β receptors at the plasma membrane. Together, both mechanisms allow for a regulated cellular response to TGF-β stimuli in mitosis.
Structures of the Signal Recognition Particle Receptor from the Archaeon Pyrococcus furiosus: Implications for the Targeting Step at the Membrane  [PDF]
Pascal F. Egea, Hiro Tsuruta, Gladys P. de Leon, Johanna Napetschnig, Peter Walter, Robert M. Stroud
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003619
Abstract: In all organisms, a ribonucleoprotein called the signal recognition particle (SRP) and its receptor (SR) target nascent proteins from the ribosome to the translocon for secretion or membrane insertion. We present the first X-ray structures of an archeal FtsY, the receptor from the hyper-thermophile Pyrococcus furiosus (Pfu), in its free and GDP?magnesium-bound forms. The highly charged N-terminal domain of Pfu-FtsY is distinguished by a long N-terminal helix. The basic charges on the surface of this helix are likely to regulate interactions at the membrane. A peripheral GDP bound near a regulatory motif could indicate a site of interaction between the receptor and ribosomal or SRP RNAs. Small angle X-ray scattering and analytical ultracentrifugation indicate that the crystal structure of Pfu-FtsY correlates well with the average conformation in solution. Based on previous structures of two sub-complexes, we propose a model of the core of archeal and eukaryotic SRP?SR targeting complexes.
Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management
Ho AS, Turcan S, Chan TA
OncoTargets and Therapy , 2013, DOI: http://dx.doi.org/10.2147/OTT.S34680
Abstract: enetic therapy: use of agents targeting deacetylation and methylation in cancer management Review (15) Total Article Views Authors: Ho AS, Turcan S, Chan TA Published Date March 2013 Volume 2013:6 Pages 223 - 232 DOI: http://dx.doi.org/10.2147/OTT.S34680 Received: 31 January 2013 Accepted: 25 February 2013 Published: 21 March 2013 Allen S Ho,1 Sevin Turcan,1 Timothy A Chan1,2 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Abstract: The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.
Epigenetic Alterations at Genomic Loci Modified by Gene Targeting in Arabidopsis thaliana  [PDF]
Michal Lieberman-Lazarovich, Cathy Melamed-Bessudo, Sylvia de Pater, Avraham A. Levy
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0085383
Abstract: Gene Targeting (GT) is the integration of an introduced vector into a specific chromosomal site, via homologous recombination. It is considered an effective tool for precise genome editing, with far-reaching implications in biological research and biotechnology, and is widely used in mice, with the potential of becoming routine in many species. Nevertheless, the epigenetic status of the targeted allele remains largely unexplored. Using GT-modified lines of the model plant Arabidopsis thaliana, we show that the DNA methylation profile of the targeted locus is changed following GT. This effect is non-directional as methylation can be either completely lost, maintained with minor alterations or show instability in the generations subsequent to GT. As DNA methylation is known to be involved in several cellular processes, GT-related alterations may result in unexpected or even unnoticed perturbations. Our analysis shows that GT may be used as a new tool for generating epialleles, for example, to study the role of gene body methylation. In addition, the analysis of DNA methylation at the targeted locus may be utilized to investigate the mechanism of GT, many aspects of which are still unknown.
Epigenetic Therapy in Lung Cancer  [PDF]
Stephen V. Liu,Muller Fabbri,Barbara J. Gitlitz,Ite A. Laird-Offringa
Frontiers in Oncology , 2013, DOI: 10.3389/fonc.2013.00135
Abstract: Epigenetic deregulation of gene function has been strongly implicated in carcinogenesis and is one of the mechanisms contributing to the development of lung cancer. The inherent reversibility of epigenetic alterations makes them viable therapeutic targets. Here, we review the therapeutic implications of epigenetic changes in lung cancer, and recent advances in therapeutic strategies targeting DNA methylation and histone acetylation.
Therapeutic Implications of Targeting AKT Signaling in Melanoma  [PDF]
SubbaRao V. Madhunapantula,Gavin P. Robertson
Enzyme Research , 2011, DOI: 10.4061/2011/327923
Abstract: Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted. 1. Introduction Kinases and phosphatases are the key components of signaling cascades regulating metabolic processes such as cell survival, proliferation, apoptosis, differentiation, and cell motility [1–4]. Aberrant expression and activities of these enzymes have been reported to lead to the development of several cancers including melanoma [4–10]. Due to genetic and epigenetic modifications, deregulating oncogenic kinases and tumor inhibitory proteins, melanocytes acquire transformed characteristics leading to malignant melanoma [4–10]. Members of the PI3K and Akt3 signaling cascades have been implicated in initiation, progression, invasive, and drug resistance phenotypes of melanomas [1–4]. Enzymes in this signaling cascade are therefore attractive targets for treating or preventing melanoma development [11–13]. This paper provides an overview of enzymes involved in PI3K-Akt signaling pathway focusing specifically on the tumor suppressor phosphatase PTEN, lipid kinase PI3K, and the oncogenic survival kinase Akt3. Key structural features, mechanisms regulating the expressionm and activities of these proteins as well as therapeutic implications of targeting this pathway to treat melanoma are reviewed. 1.1. Tumor Suppressor PTEN Is a Key Phosphatase Regulating PI3K-Akt3 Signaling and Thereby Melanoma
Epigenetic Regulation of Thyroid Hormone Receptor Beta in Renal Cancer  [PDF]
Anna Wojcicka, Agnieszka Piekielko–Witkowska, Hanna Kedzierska, Beata Rybicka, Piotr Poplawski, Joanna Boguslawska, Adam Master, Alicja Nauman
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097624
Abstract: Thyroid hormone receptor beta (THRB) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of THRB in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of THRB in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in THRB and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However, THRB CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples. In silico analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting THRB transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3′UTR of THRB, and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous TRHB by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of THRB transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased THRB expression in ccRCC. In contrast, THRB is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of THRB in ccRCC tumors.
Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management
Ho AS,Turcan S,Chan TA
OncoTargets and Therapy , 2013,
Abstract: Allen S Ho,1 Sevin Turcan,1 Timothy A Chan1,2 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Abstract: The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy. Keywords: epigenetics, cancer, acetylation, methylation, histone, transcription, tumor
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