116 research outputs found
The confirmability and disconfirmability of trait concepts revisited: does content matter?
No full textM. Rothbart and B. Park (1986) demonstrated that, consistent with the common negativity bias, positive traits are difficult to confirm and easy to disconfirm, whereas the opposite is true for negative traits. This article extends their analysis by showing that trait (dis-)confirmability is moderated by trait content (warmth vs. competence). Study 1 identifies a trait sample representative of warmth and competence. Study 2 shows a strong negativity effect for warmth and a reduced (or absent) negativity effect for competence. Study 3 examines trait properties related to the behavioral range of the trait possessor and to the motivational goals of the perceiver as predictors of trait (dis-)confirmability. The theoretical and practical implications of the authors' findings are discussed, and avenues for future research are suggested
A Histone Methylation Network Regulates Transgenerational Epigenetic Memory in C. elegans
No full textSummaryHow epigenetic information is transmitted from generation to generation remains largely unknown. Deletion of the C. elegans histone H3 lysine 4 dimethyl (H3K4me2) demethylase spr-5 leads to inherited accumulation of the euchromatic H3K4me2 mark and progressive decline in fertility. Here, we identified multiple chromatin-modifying factors, including H3K4me1/me2 and H3K9me3 methyltransferases, an H3K9me3 demethylase, and an H3K9me reader, which either suppress or accelerate the progressive transgenerational phenotypes of spr-5 mutant worms. Our findings uncover a network of chromatin regulators that control the transgenerational flow of epigenetic information and suggest that the balance between euchromatic H3K4 and heterochromatic H3K9 methylation regulates transgenerational effects on fertility
Interpreting the language of histone and DNA modifications
No full textA major mechanism regulating the accessibility and function of eukaryotic genomes are the covalent modifications to DNA and histone proteins that dependably package our genetic information inside the nucleus of every cell. Formally postulated over a decade ago, it is becoming increasingly clear that post-translational modifications (PTMs) on histones act singly and in combination to form a language or ‘code’ that is read by specialized proteins to facilitate downstream functions in chromatin. Underappreciated at the time was the level of complexity harbored both within histone PTMs and their combinations, as well as within the proteins that read and interpret the language. In addition to histone PTMs, newly-identified DNA modifications that can recruit specific effector proteins has raised further awareness that histone PTMs operate within a broader language of epigenetic modifications to orchestrate the dynamic functions associated with chromatin. Here, we highlight key recent advances in our understanding of the epigenetic language encompassing histone and DNA modifications and foreshadow challenges that lie ahead as we continue our quest to decipher the fundamental mechanisms of chromatin regulation
Pemetrexed Indirectly Activates the Metabolic Kinase AMPK in Human Carcinomas
No full textAbstract
The chemotherapeutic drug pemetrexed, an inhibitor of thymidylate synthase, has an important secondary target in human leukemic cells, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), the second folate-dependent enzyme of purine biosynthesis. The purine intermediate aminoimidazolecarboxamide ribonucleotide (ZMP), which accumulates behind this block, transmits an inhibitory signal to the mTORC1 complex via activation of the cellular energy sensor AMP-activated kinase (AMPK). Given that the PI3K-AKT-mTOR pathway is frequently deregulated during carcinogenesis, we asked whether the indirect activation of AMPK by pemetrexed offers an effective therapeutic strategy for carcinomas with defects in this pathway. Activation of AMPK by ZMP in pemetrexed-treated colon and lung carcinoma cells and the downstream consequences of this activation were strikingly more robust than previously seen in leukemic cells. Genetic experiments demonstrated the intermediacy of AICART inhibition and the centrality of AMPK activation in these effects. Whereas AMPK activation resulted in marked inhibition of mTORC1, other targets of AMPK were phosphorylated that were not mTORC1-dependent. Whereas AMPK activation is thought to require AMPKα T172 phosphorylation, pemetrexed also activated AMPK in carcinoma cells null for LKB1, the predominant AMPKα T172 kinase whose deficiency is common in lung adenocarcinomas. Like rapamycin analogs, pemetrexed relieved feedback suppression of PI3K and AKT, but the prolonged accumulation of unphosphorylated 4E-BP1, a tight-binding inhibitor of cap-dependent translation, was seen following AMPK activation. Our findings indicate that AMPK activation by pemetrexed inhibits mTORC1-dependent and -independent processes that control translation and lipid metabolism, identifying pemetrexed as a targeted therapeutic agent for this pathway that differs significantly from rapamycin analogs. Cancer Res; 70(24); 10299–309. ©2010 AACR.</jats:p
Abstract 5086: Pemetrexed induces a strong activation of AMPK in human carcinoma cells, even in the absence of LKB1
No full textAbstract
AMP-activated protein kinase (AMPK) is a major cellular energy sensor, functioning as a regulator of signaling cascades controlling protein, lipid, and carbohydrate metabolism. Because of the dependence of many tumors on the deregulation of the PI3K-AKT-mTOR signaling cascade, the discovery of AMPK activators is an attractive approach for cancer therapeutics, aimed at reinstating control over cellular metabolic functions altered during carcinogenesis rather than inhibiting cellular targets. The antifolate pemetrexed is FDA approved for first line treatment of mesothelioma and non-small cell lung cancer (NSCLC). While pemetrexed acts primarily as a thymidylate synthase inhibitor, we discovered that the drug is also an inhibitor of aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), the second folate-dependent enzyme of de novo purine synthesis. The inhibition of AICART by pemetrexed resulted in a marked accumulation of the reaction substrate, ZMP, a known allosteric activator of AMPK in several human carcinoma cell lines. The mammalian target of rapamycin complex 1 (mTORC1) was inhibited following pemetrexed treatment, as determined by hypophosphorylation of S6K1 and 4EBP1, and this effect was dependent on AMPK activation. Co-administration of GSK690693, a pan AKT inhibitor prolonged mTORC1 inhibition following pemetrexed treatment and offset the consequences of negative feedback activation of mTORC1 through PI3-kinase and mTORC2 activity. Interestingly, cells insensitive to mTORC1 inhibition following AMPK activation retained sensitivity to the secondary effect of pemetrexed, apparently due to inhibition of lipid synthesis through phosphorylation of acetyl-CoA carboxylase by AMPK. We concluded that the growth inhibitory effect of pemetrexed following AMPK activation in human carcinoma cells was due to a combined effect of inhibition of mTORC1 signaling and lipogenesis, both of which were mediated by activation of AMPK. Somewhat surprisingly, several cell lines null for LKB1, the major upstream kinase of AMPK, retained sensitivity to the secondary effects of pemetrexed mediated through AMPK activation. This suggests that the effect of pemetrexed on AMPK activity will be preserved in tumors lacking LKB1, a common genotype of human NSCLC. Hence, pemetrexed exerts its effects on carcinoma cells by both inhibition of traditional antifolate targets and by a novel mechanism, activation of AMPK. (Supported in part by NIH Grant CA-27605)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5086.</jats:p
Lysine Methylation Regulators Moonlighting outside the Epigenome
No full textInternational audienceLandmark discoveries made nearly two decades ago identified known transcriptional regulators as histone lysine methyltransferases. Since then, the field of lysine methylation signaling has been dominated by studies of how this small chemical posttranslational modification regulates gene expression and other chromatin-based processes. However, recent advances in mass-spectrometry-based proteomics have revealed that histones are just a subset of the thousands of eukaryotic proteins marked by lysine methylation. As the writers, erasers, and readers of histone lysine methylation are emerging as a promising therapeutic target class for cancer and other diseases, a key challenge for the field is to define the full spectrum of activities for these proteins. Here we summarize recent discoveries implicating non-histone lysine methylation as a major regulator of diverse cellular processes. We further discuss recent technological innovations that are enabling the expanded study of lysine methylation signaling. Collectively, these findings are shaping our understanding of the fundamental mechanisms of non-histone protein regulation through this dynamic and multi-functional posttranslational modification
Does emotion dysregulation mediate the relationship between behavioural inhibition and psychopathological symptoms?
No full textFailure to address poor mental health during childhood and adolescence results in higher risk of suicide, substance misuse, self-harm, and lower achievement in education and employment (Richards et al., 2009). Of the psychological factors underlying mental health, it has been argued that self-regulation is central (Posner & Rothbart, 2000). The Barkley (1997) model of self-regulation is reviewed, and evidence considered that suggests it has cross-diagnostic validity. The typical developmental courses of emotion regulation and effortful control, and how these are associated with mental health, are considered in order to inform applied psychology practice with children and young people. A refinement of the Barkley model is proposed to enable the synthesis of findings from different bodies of research, and to offer a framework by which psychopathological diagnoses might be etiologically, rather than behaviourally, defined.The research study used neuropsychological and self-report measures to test whether emotion dysregulation mediated the relationship between behavioural inhibition and psychopathological symptoms in adolescents. 39 pupils, aged 10 to 16 years, completed sustained attention subtests from the Test of Everyday Attention, the Attentional Control Scale, Difficulties in Emotion Regulation Scale, the Aggression Scale and the Strengths and Difficulties Questionnaire. Adult-report versions of the Strengths and Difficulties Questionnaire were also completed by parents and teachers. Significant, positive correlations between difficulties in emotion regulation and psychopathological symptoms were observed. Significant negative correlations were observed between behavioural inhibition and psychopathological symptoms. The mediation model was supported: emotion dysregulation fully mediated the relationship between behavioural inhibition and psychopathological symptoms. The relationship of the study results to the Barkley (1997) model of self-regulation is discussed. The study findings suggest that intervention to treat or prevent the development of psychopathological symptoms in adolescents is better targeted at reducing habits of emotion dysregulation than at improving the capacity for behavioural inhibition
Author response
No full textThe epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. HeDNA recognition activates UHRF1 ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies are the first demonstrations of a DNA-protein interaction and an epigenetic modification directly regulating E3 ubiquitin ligase activity. They also define an orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance
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