A Novel Mechanism for CTCF in the Epigenetic Regulation of Bax in Breast Cancer Cells

Wepreviously reported the association of elevated levels of themultifunctional transcription factor, CCCTC binding factor (CTCF), in breast cancer cells with the specific anti-apoptotic function of CTCF. To understand the molecularmechanisms of this phenomenon, we investigated regulation of the human Bax gene by CTCF in breast and non-breast cells. Two CTCF binding sites (CTSs) within the Bax promoter were identified. In all cells, breast and non-breast, active histone modifications were present at these CTSs, DNA harboring this region was unmethylated, and levels of Bax mRNA and protein were similar. Nevertheless, up-regulation of Bax mRNA and protein and apoptotic cell deathwere observed only in breast cancer cells depleted of CTCF.We proposed that increased CTCF binding to the Bax promoter in breast cancer cells, by comparison with non-breast cells, may be mechanistically linked to the specific apoptotic phenotype in CTCF-depleted breast cancer cells. In this study, we show that CTCF binding was enriched at the Bax CTSs in breast cancer cells and tumors; in contrast, binding of other transcription factors (SP1,WT1, EGR1, and c-Myc) was generally increased in non- breast cells and normal breast tissues. Our findings suggest a novel mechanism for CTCF in the epigenetic regulation of Bax in breast cancer cells, whereby elevated levels of CTCF support preferential binding of CTCF to the Bax CTSs. In this context, CTCF functions as a transcriptional repressor counteracting influences of positive regulatory factors; depletion of breast cancer cells from CTCF therefore results in the activation of Bax and apoptosis. © 2013 Neoplasia Press, Inc

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53−/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence

Prognostische Bedeutung des p53/Bax/p16 INK4a -Signalwegs bei Patienten mit kolorektalem Karzinom

Die Dysregulation von Zelltod-Signalwegen und die Inaktivierung von Apoptose-Signalwegen ist ein häufiges Ereignis bei der Entstehung maligner Tumore. Ziel dieser dieser Studie war es den prognostischen Wert der Bax- und p16INK4a-Proteinexpression in Korrelation zum Mutationsstatus des p53-Gens bei Patienten in einem Kollektiv von primären kolorektalen Adenokarzinom zu analysieren. Methoden: Retrospektiv wurden 116 Patienten mit einem kolorektalen Karzinom (CRC) im Stadium III und IV nach operativer Therapie und follow-up über 5 Jahre untersucht (UICC Stadium III: 59 Patienten; UICC Stadium IV: 57 Patienten). Die Profile der Bax- und p16INK4a-Proteinexpression wurden mittels Immunhistochemie, die p53-Mutationen (Exon 5 - 8) mittels Single Strand Conformation Polymorphism (SSCP)-PCR untersucht. Die gewonnenen Daten wurden mit klinisch-pathologischen Daten korreliert und statistisch analysiert Ergebnisse: Das mediane Gesamtüberleben betrug 17 Monate. Patienten im Stadium III lebten länger als solche im Stadium IV: 69 vs. acht Monate (pDeregulation of cell death and cell cycle regulation pathways is a frequent event in cancer. Therefore, the purpose of this study was to analyse the prognostic value of Bax and p16INK4a protein expression in correlation to the mutational status of the p53 tumorsuppressor gene in primary colorectal adenocarcinoma. Methods: 116 patients with colorectal adenocarcinoma (CRC) undergoing surgery with curative intention a followed-up for a minimum of five years were analyzed (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Protein expression profiles of Bax and p16INK4a were analysed by immunhistochemistry, the p53-mutations (exon 5 - 8) by Single-Strand-Conformation-Polymorphism (SSCP)-PCR. Data was correltated with clinical and pathological parameters and analysed statistically. Results: Overall median survival was 17 months. As expected, patients with stage III malignancies survived longer than stage IV patients: 69 months vs. 8 months (

A Spectral Visualization System for Analyzing Financial Time Series Data

Visual data analysis of time related data sets has attracted much research interest recently, and a number of sophisticated visualization methods have been proposed in the past. In financial analysis, however, the most important and most common visualization techniques for time series data is the traditional line- or bar chart. Although these are intuitive and make it easy to spot the effect of key events on a asset s price, and its return over a given period of time, price charts do not allow the easy perception of relative movements in terms of growth rates, which is the key feature of any price-related time series. This paper presents a novel Growth Matrix visualization technique for analyzing assets. It extends the ability of existing chart techniques by not only visualizing asset return rates over fixed time frames, but over the full spectrum of all subintervals present in a given time frame, in a single view. At the same time, the technique allows a comparison of subinterval return rates among groups of even a few hundreds of assets. This provides a powerful way for analyzing financial data, since it allows the identification of strong and weak periods of assets as compared to global market characteristics, and thus allows a more encompassing visual classification into good and poor" performers than existing chart techniques. We illustrate the technique by real-world examples showing the abilities of the new approach, and its high relevance for financial analysis tasks

Site-Selective Hydrogenation of Electron-Poor Alkenes and Dienes Enabled by a Rh-Catalyzed Hydride Addition/Protonolysis Mechanism

The transition metal catalyzed hydrogenation of alkenes is a well-developed technology used on a lab scale as well as on large scales in the chemical industry. Site- and chemoselective mono-hydrogenations of polarized conjugated dienes remain challenging. Instead, stoichiometric main-group hydrides are used rather than H2. As part of an effort to develop a scalable route to prepare geranylacetone, we discovered that Rh(CO)2acac/xantphos based catalysts enable the selective monohydrogenation of electron-poor 1,3-dienes, enones, and other polyunsaturated substrates. D-labeling and DFT studies support a mechanism where a nucleophilic Rh(I)-hydride selectively adds to electron-poor alkenes and the resulting Rh-enolate undergoes subsequent inner-sphere protonation by alcohol solvent. The finding that (Ln)Rh(H)(CO) type catalysts can enable selective mono-hydrogenation of electron-poor (poly)enes provides a valuable tool in the design of related chemoselective reduction processes of unsaturated substrates