The ETS Family Member TEL Binds to Nuclear Receptors RAR and RXR and Represses Gene Activation

Retinoic acid receptor (RAR) signaling is important for regulating transcriptional activity of genes involved in growth, differentiation, metabolism and reproduction. Defects in RAR signaling have been implicated in cancer. TEL, a member of the ETS family of transcription factors, is a DNA-binding transcriptional repressor. Here, we identify TEL as a transcriptional repressor of RAR signaling by its direct binding to both RAR and its dimerisation partner, the retinoid x receptor (RXR) in a ligand-independent fashion. TEL is found in two isoforms, created by the use of an alternative startcodon at amino acid 43. Although both isoforms bind to RAR and RXR in vitro and in vivo, the shorter form of TEL represses RAR signaling much more efficiently. Binding studies revealed that TEL binds closely to the DNA binding domain of RAR and that both Helix Loop Helix (HLH) and DNA binding domains of TEL are mandatory for interaction. We have shown that repression by TEL does not involve recruitment of histone deacetylases and suggest that polycomb group proteins participate in the process

Heat shock protein-90-alpha, a prolactin-STAT5 target gene identified in breast cancer cells, is involved in apoptosis regulation

Introduction The prolactin-Janus-kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) pathway is essential for the development and functional differentiation of the mammary gland. The pathway also has important roles in mammary tumourigenesis. Prolactin regulated target genes are not yet well defined in tumour cells, and we undertook, to the best of our knowledge, the first large genetic screen of breast cancer cells treated with or without exogenous prolactin. We hypothesise that the identification of these genes should yield insights into the mechanisms by which prolactin participates in cancer formation or progression, and possibly how it regulates normal mammary gland development. Methods We used subtractive hybridisation to identify a number of prolactin-regulated genes in the human mammary carcinoma cell line SKBR3. Northern blotting analysis and luciferase assays identified the gene encoding heat shock protein 90-alpha (HSP90A) as a prolactin-JAK2-STAT5 target gene, whose function was characterised using apoptosis assays. Results We identified a number of new prolactin-regulated genes in breast cancer cells. Focusing on HSP90A, we determined that prolactin increased HSP90A mRNA in cancerous human breast SKBR3 cells and that STAT5B preferentially activated the HSP90A promoter in reporter gene assays. Both prolactin and its downstream protein effector, HSP90α, promote survival, as shown by apoptosis assays and by the addition of the HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in both untransformed HC11 mammary epithelial cells and SKBR3 breast cancer cells. The constitutive expression of HSP90A, however, sensitised differentiated HC11 cells to starvation-induced wild-type p53-independent apoptosis. Interestingly, in SKBR3 breast cancer cells, HSP90α promoted survival in the presence of serum but appeared to have little effect during starvation. Conclusions In addition to identifying new prolactin-regulated genes in breast cancer cells, we found that prolactin-JAK2-STAT5 induces expression of the HSP90A gene, which encodes the master chaperone of cancer. This identifies one mechanism by which prolactin contributes to breast cancer. Increased expression of HSP90A in breast cancer is correlated with increased cell survival and poor prognosis and HSP90α inhibitors are being tested in clinical trials as a breast cancer treatment. Our results also indicate that HSP90α promotes survival depending on the cellular conditions and state of cellular transformation

Heterogeneity of Microglial Activation in the Innate Immune Response in the Brain

The immune response in the brain has been widely investigated and while many studies have focused on the proinflammatory cytotoxic response, the brain’s innate immune system demonstrates significant heterogeneity. Microglia, like other tissue macrophages, participate in repair and resolution processes after infection or injury to restore normal tissue homeostasis. This review examines the mechanisms that lead to reduction of self-toxicity and to repair and restructuring of the damaged extracellular matrix in the brain. Part of the resolution process involves switching macrophage functional activation to include reduction of proinflammatory mediators, increased production and release of anti-inflammatory cytokines, and production of cytoactive factors involved in repair and reconstruction of the damaged brain. Two partially overlapping and complimentary functional macrophage states have been identified and are called alternative activation and acquired deactivation. The immunosuppressive and repair processes of each of these states and how alternative activation and acquired deactivation participate in chronic neuroinflammation in the brain are discussed

The convergent validity of Actiwatch 2 and ActiGraph Link accelerometers in measuring total sleeping period, wake after sleep onset, and sleep efficiency in free-living condition

Physical activity (PA) and sleep are important to health; thus, it is important for researchers to have valid tools to measure them. Accelerometers have been proven valid for measuring PA and sleep, but only one device does this simultaneously: the ActiGraph Link (ActiGraph, LLC); however, the sleep-monitoring function has not been validated. This study aimed to evaluate the predictive power of ActiGraph Link sleep parameters against a validated accelerometer (Actiwatch 2, Phillips Respironics Mini-Mitter). A total of 49 Hong Kong adults aged 18-64 provided valid data on both accelerometers on their non-dominant wrist for seven consecutive days. Epochs from both accelerometers were classified as either sleep or awake using seven established algorithms (Cole-Kripke, Sadeh, Sazonov, high sensitivity threshold, medium sensitivity threshold, low sensitivity threshold, and neural network model), and these data were transformed to total sleeping period, wake after sleep onset, and sleep efficiency. The non-zero count data for both accelerometers (331,103 observations) were strongly correlated with a Spearman correlation of 0.83 (p < 0.001). The total sleeping period was highly correlated (Spearman correlation ranged from 0.74 to 0.90) regardless of the algorithms used. All algorithms yielded insignificant difference in total sleep time measured by the two accelerometers (p > 0.05) with a negligible effect size of d < 0.2. The agreement of sleep/wake status was high for all algorithms, with accuracy ranging from 93.05 % (Sadeh's algorithm) to 96.13 % (Cole-Kripke's algorithm). Results showed that the sleep function of the ActiGraph Link performs similar to a validated accelerometer (Actiwatch 2) and provides an opportunity to measure both sleep and PA simultaneously.School of Nursing2016-2017 > Academic research: refereed > Publication in refereed journalbcr

Attachment to Conventional Institutions and Adolescent Rapid Repeat Pregnancy: A Longitudinal National Study Among Adolescents in the United States

INTRODUCTION: There is limited research on rapid repeat pregnancies (RRP) among adolescents, especially using nationally representative samples. We examine distal factors—school, family, peers, and public/private religious ties—and their associations with RRP among adolescent mothers. METHODS: Guided by social development theory, we conducted multivariate logistic regression analyses, adjusted for sociodemographic characteristics, to examine associations between RRP and attachment to school, family, peers, and religion among 1,158 female respondents from the National Longitudinal Study of Adolescent to Adult Health (Add Health) who reported at least one live birth before age 20. RESULTS: Attachments to conventional institutions were associated with lower likelihood of RRP. Adolescent mothers who had a stronger relationship with their parents had reduced odds of RRP (adjusted odds ratio [aOR] 0.83, 95% CI 0.71-0.99). Increased odds of RRP were associated with anticipating fewer negative social consequences of sex (aOR 1.18, 95% CI 1.02-1.35), never praying (versus praying daily; aOR 1.47, 95% CI 1.10-1.96), and never participating in church-related youth activities (versus participating once a week; 1.04, 95% CI 1.01-1.07). DISCUSSION: After an adolescent birth, social support from family, peers, and the community can benefit young mothers. Private aspects of religiosity may be especially important. Understanding the processes by which these distal factors are linked to the likelihood of RRP is needed to create multifaceted intervention programs that provide diverse methods of support customized to specific circumstances of adolescent mothers