Active heat shock transcription factor 1 supports migration of the melanoma cells via vinculin down-regulation

AbstractHeat shock transcription factor 1 (HSF1), the major regulator of stress response, is frequently activated in cancer and has an apparent role in malignant transformation. Here we analyzed the influence of the over-expression of a constitutively active transcriptionally-competent HSF1 mutant form on phenotypes of mouse and human melanoma cells. We observed that the expression of active HSF1 supported anchorage-independent growth in vitro, and metastatic spread in the animal model in vivo, although the proliferation rate of cancer cells was not affected. Furthermore, active HSF1 enhanced cell motility, reduced the adherence of cells to a fibronectin-coated surface, and affected the actin cytoskeleton. We found that although the expression of active HSF1 did not affect levels of epithelial-to-mesenchymal transition markers, it caused transcriptional down-regulation of vinculin, protein involved in cell motility, and adherence. Functional HSF1-binding sites were found in mouse and human Vcl/VCL genes, indicating a direct role of HSF1 in the regulation of this gene. An apparent association between HSF1-induced down-regulation of vinculin, increased motility, and a reduced adherence of cells suggests a possible mechanism of HSF1-mediated enhancement of the metastatic potential of cancer cells

Heat shock factor 1 (Hsf1) cooperates with estrogen receptor α (erα) in the regulation of estrogen action in breast cancer cells

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from The Cancer Genome Atlas database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers an elevated HSF1 level is associated with metastatic disease.publishedVersio

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Simus ergo Hilares. Several Words about Epic Poems in the Interpretation of Homerists

At the beginning of the Hellenistic era, Greek theatre became a universal entertainment in the whole oikumene, and some of the reasons for this cultural success were the changes inside the genres and series of reforms in the theatrical practice, among which very important was the development of mime. The aim of this paper is to present a detailed analysis of the ancient sources relating to the performances of homeristai, the most important of which are the Deipnosophists of Athenaeus, Satiricon of Petronius and five papyri: P.Oxy. 519, 1.4; P.Oxy. 10.25, 1.8; P.Oxy. 1050, 1.26; SB 7336 1.26 et 29; P.Oslo 189 verso. I try to re-examine all the testimonies to present a coherent picture of this type of mime, and investigate its origins, its theatrical practice and the social status of its actors. Central in this discussion is the question of parodist nature of these performances. The widely accepted opinion of burlesque character of the homerists’ shows is at odds with the ancient testimonia, which in most cases do not attest their nature. The main testimony for the ludic character of the performances is Petronius’ Satiricon. However, the work which seeks to ridicule Trimalchio by means of grotesque exaggeration is not a credible source for determining the nature of these presentations. The source of humour is not a distortion of Iliad by homeristai but Trimalchio’s absurd translation and travesty of the text. Another important topic of this paper is the actual text used during the performances. Giving priority to the role of dialogue in the performances, I refuse the concept of homeristai playing a pantomime and I present possible “sripts”, suggested by scholars, among which the most probable is P. Koln. VI 245.The aim of this paper is to present a detailed picture of homeristai, the characteristic of the artists who have been specialized in acting the scenes from Greek epic. It focuses on analysing the ancient sources relating to their performances, and examines whether they had a burlesque or a more serious character. By providing information on different aspects of the art of acting and the possible text used by homeristai, I try to reconstruct the performances and their significance in the late Greek theatre

„Jeśli jeszcze tylko zabijemy starca...” Farsa kryminalna w teatrze grecko-rzymskim w Egipcie (POxy. 413 verso)

This paper presents a translatory proposition of the mime preserved on POxy. 413 verso (Moicheutria) into Polish, along with a concise analysis of the theatrical and literary issues that are observed in this ancient genre.This paper presents a translatory proposition of the mime preserved on POxy. 413 verso (Moicheutria) into Polish, along with a concise analysis of the theatrical and literary issues that are observed in this ancient genre