Cellular stress-induced up-regulation of FMRP promotes cell survival by modulating PI3K-Akt phosphorylation cascades

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS), the most commonly inherited mental retardation and single gene cause of autistic spectrum disorder, occurs when the Fmr1 gene is mutated. The product of Fmr1, fragile X linked mental retardation protein (FMRP) is widely expressed in HeLa cells, however the roles of FMRP within HeLa cells were not elucidated, yet. Interacting with a diverse range of mRNAs related to cellular survival regulatory signals, understanding the functions of FMRP in cellular context would provide better insights into the role of this interesting protein in FXS. Using HeLa cells treated with etoposide as a model, we tried to determine whether FMRP could play a role in cell survival.</p> <p>Methods</p> <p>Apoptotic cell death was induced by etoposide treatment on Hela cells. After we transiently modulated FMRP expression (silencing or enhancing) by using molecular biotechnological methods such as small hairpin RNA virus-induced knock down and overexpression using transfection with FMRP expression vectors, cellular viability was measured using propidium iodide staining, TUNEL staining, and FACS analysis along with the level of activation of PI3K-Akt pathway by Western blot. Expression level of FMRP and apoptotic regulator BcL-xL was analyzed by Western blot, RT-PCR and immunocytochemistry.</p> <p>Results</p> <p>An increased FMRP expression was measured in etoposide-treated HeLa cells, which was induced by PI3K-Akt activation. Without FMRP expression, cellular defence mechanism via PI3K-Akt-Bcl-xL was weakened and resulted in an augmented cell death by etoposide. In addition, FMRP over-expression lead to the activation of PI3K-Akt signalling pathway as well as increased FMRP and BcL-xL expression, which culminates with the increased cell survival in etoposide-treated HeLa cells.</p> <p>Conclusions</p> <p>Taken together, these results suggest that FMRP expression is an essential part of cellular survival mechanisms through the modulation of PI3K, Akt, and Bcl-xL signal pathways.</p

The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma

<p>Abstract</p> <p>Background</p> <p><it>Klotho </it>was originally characterized as an anti-aging gene that predisposed Klotho-deficient mice to a premature aging-like syndrome. Recently, KLOTHO was reported to function as a secreted Wnt antagonist and as a tumor suppressor. Epigenetic gene silencing of secreted Wnt antagonists is considered a common event in a wide range of human malignancies. Abnormal activation of the canonical Wnt pathway due to epigenetic deregulation of Wnt antagonists is thought to play a crucial role in cervical tumorigenesis. In this study, we examined epigenetic silencing of <it>KLOTHO </it>in human cervical carcinoma.</p> <p>Results</p> <p>Loss of <it>KLOTHO </it>mRNA was observed in several cervical cancer cell lines and in invasive carcinoma samples, but not during the early, preinvasive phase of primary cervical tumorigenesis. <it>KLOTHO </it>mRNA was restored after treatment with either the DNA demethylating agent 2'-deoxy-5-azacytidine or histone deacetylase inhibitor trichostatin A. Methylation-specific PCR and bisulfite genomic sequencing analysis of the promoter region of <it>KLOTHO </it>revealed CpG hypermethylation in non-<it>KLOTHO</it>-expressing cervical cancer cell lines and in 41% (9/22) of invasive carcinoma cases. Histone deacetylation was also found to be the major epigenetic silencing mechanism for <it>KLOTHO </it>in the SiHa cell line. Ectopic expression of the secreted form of KLOTHO restored anti-Wnt signaling and anti-clonogenic activity in the CaSki cell line including decreased active β-catenin levels, suppression of T-cell factor/β-catenin target genes, such as <it>c-MYC </it>and <it>CCND1</it>, and inhibition of colony growth.</p> <p>Conclusions</p> <p>Epigenetic silencing of <it>KLOTHO </it>may occur during the late phase of cervical tumorigenesis, and consequent functional loss of KLOTHO as the secreted Wnt antagonist may contribute to aberrant activation of the canonical Wnt pathway in cervical carcinoma.</p

Altered Metabolic Phenotypes and Hypothalamic Neuronal Activity Triggered by Sodium-Glucose Cotransporter 2 Inhibition

Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are currently used to treat patients with diabetes. Previous studies have demonstrated that treatment with SGLT-2 inhibitors is accompanied by altered metabolic phenotypes. However, it has not been investigated whether the hypothalamic circuit participates in the development of the compensatory metabolic phenotypes triggered by the treatment with SGLT-2 inhibitors. Methods Mice were fed a standard diet or high-fat diet and treated with dapagliflozin, an SGLT-2 inhibitor. Food intake and energy expenditure were observed using indirect calorimetry system. The activity of hypothalamic neurons in response to dapagliflozin treatment was evaluated by immunohistochemistry with c-Fos antibody. Quantitative real-time polymerase chain reaction was performed to determine gene expression patterns in the hypothalamus of dapagliflozin-treated mice. Results Dapagliflozin-treated mice displayed enhanced food intake and reduced energy expenditure. Altered neuronal activities were observed in multiple hypothalamic nuclei in association with appetite regulation. Additionally, we found elevated immunosignals of agouti-related peptide neurons in the paraventricular nucleus of the hypothalamus. Conclusion This study suggests the functional involvement of the hypothalamus in the development of the compensatory metabolic phenotypes induced by SGLT-2 inhibitor treatment

Spatial and temporal variabilities of spring Asian dust events and their impacts on chlorophyll-a concentrations in the western North Pacific Ocean

Author Posting. © American Geophysical Union, 2017. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 44 (2017): 1474–1482, doi:10.1002/2016GL072124.As the western North Pacific Ocean is located downwind of the source regions for spring Asian dust, it is an ideal location for determining the response of open waters to these events. Spatial analysis of spring Asian dust events from source regions to the western North Pacific, using long-term daily aerosol index data, revealed three different transport pathways supported by the westerly wind system: one passing across the northern East/Japan Sea (40°N–50°N), a second moving over the entire East/Japan Sea (35°N–55°N), and a third flowing predominantly over the Siberian continent (>50°N). Our results indicate that strong spring Asian dust events can increase ocean primary productivity by more than 70% (>2-fold increase in chlorophyll-a concentrations) compared to weak/nondust conditions. Therefore, attention should be paid to the recent downturn in the number of spring Asian dust events and to the response of primary production in the western North Pacific to this change.Korean government (MSIP) Grant Numbers: 2015R1C1A1A01052051, NRF-C1ABA001-2011-0021064; Korea Polar Research Institute (KOPRI) Grant Number: PE17030; NOAA Grant Number: NA11OAR4310063; WHOI2017-08-1

5.IEEE-IGARSS in Seoul, Korea

Inha UniversityAgency for Defense DevelopmentDue to the phenological variation of vegetation growth in temperate region, it is often difficult to accurately assess the surface conditions on agricultural croplands, grasslands, and disturbed forests by current multi-spectral remote sensor data. In particular, the spectral similarity between soil and dry vegetation has been primary concern to correctly appraise the surface conditions during the non-growing seasons in temperature region. This study analyzes the spectral characteristics of the mixture of dry vegetation and soil. The reflectance spectra were obtained from laboratory spectroradiometer measurement and from EO-1 Hyperion image data. The reflectance spectra of several samples having different level of dry vegetation fractions show similar pattern from both lab measurement and hyperspectral image. Shortwave IR wavelengths, in particular at wavelength near 2200nm, are more sensitive to the fraction of dry vegetation. The reflectance spectra of bare soil could be distinguished from the other surfaces covered by dry vegetation during the leaf-off season. © 2005 IEEE.Project Number 14404021, Peport of Research Project ; Grant-in-Aid for Scientific Research(B)(2), from April 2002 to March 2006, Edited by Muramoto,Ken-ichiroKamata, NaotoKawanishi, TakuyaKubo, MamoruLiu, JiyuanLee, Kyu-Sung , 人工衛星データ活用のための東アジアの植生調査、課題番号14404021, 平成14年度～平成17年度科学研究費補助金, 基盤研究（B)(2)研究成果報告書, 研究代表者：村本, 健一郎, 金沢大学自然科学研究科教