Secreted growth factors have been shown to stimulate the transcriptional activity of estrogen receptors (ER) that are responsible for many biological processes. However, whether these growth factors physically interact with ER remains unclear. Here, we show for the first time that connective tissue growth factor (CTGF) physically and functionally associates with ER. CTGF interacted with ER both in vitro and in vivo. CTGF interacted with ER DNA-binding domain. ER interaction region in CTGF was mapped to the thrombospondin type I repeat, a cell attachment motif. Overexpression of CTGF inhibited ER transcriptional activity as well as the expression of estrogen-responsive genes, including pS2 and cathepsin D. Reduction of endogenous CTGF with CTGF small interfering RNA enhanced ER transcriptional activity. The interaction between CTGF and ER is required for the repression of estrogen-responsive transcription by CTGF. Moreover, CTGF reduced ER protein expression, whereas the CTGF mutant that did not repress ER transcriptional activity also did not alter ER protein levels. The results suggested the transcriptional regulation of estrogen signaling through interaction between CTGF and ER, and thus may provide a novel mechanism by which cross-talk between secreted growth factor and ER signaling pathways occurs.
Small Heat Shock Proteins (sHSPs) are molecular chaperones that transiently interact with other proteins, thereby assisting with quality control of proper protein folding and/or degradation. They are also recruited to protect cells from a variety of stresses in response to extreme heat, heavy metals, and oxidative-reductive stress. Although ten human sHSPs have been identified, their likely diverse biological functions remain an enigma in health and disease, and much less is known about non-redundant roles in selective cells and tissues. Herein, we set out to comprehensively characterize the cardiac-restricted Heat Shock Protein B-2 (HspB2), which exhibited ischemic cardioprotection in transgenic overexpressing mice including reduced infarct size and maintenance of ATP levels. Global yeast two-hybrid analysis using HspB2 (bait) and a human cardiac library (prey) coupled with co-immunoprecipitation studies for mitochondrial target validation revealed the first HspB2 “cardiac interactome” to contain many myofibril and mitochondrial-binding partners consistent with the overexpression phenotype. This interactome has been submitted to the Biological General Repository for Interaction Datasets (BioGRID). A related sHSP chaperone HspB5 had only partially overlapping binding partners, supporting specificity of the interactome as well as non-redundant roles reported for these sHSPs. Evidence that the cardiac yeast two-hybrid HspB2 interactome targets resident mitochondrial client proteins is consistent with the role of HspB2 in maintaining ATP levels and suggests new chaperone-dependent functions for metabolic homeostasis. One of the HspB2 targets, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), has reported roles in HspB2 associated phenotypes including cardiac ATP production, mitochondrial function, and apoptosis, and was validated as a potential client protein of HspB2 through chaperone assays. From the clientele and phenotypes identified herein, it is tempting to speculate that small molecule activators of HspB2 might be deployed to mitigate mitochondrial related diseases such as cardiomyopathy and neurodegenerative disease.
The present study aimed to explore the association between SUA and NAFLD in women with different menstrual statuses.A total of 6043 women were selected from the Jidong and Kailuan communities for inclusion in the present study. The SUA levels of participants were divided into quartiles. NAFLD was determined by abdominal ultrasonography. Data from laboratory tests and clinical examination were collected, and basic information was obtained from standardized questionnaires. The menstrual status was stratified into menstrual period, menopause transition period, and postmenopause. Multivariate logistic regression models were used to determine the relationship between menstrual status, SUA, and NAFLD.The levels of SUA in subjects with NAFLD in the menstrual period, menopause transition period, and postmenopause were 268.0 ± 71.1, 265.6 ± 67.8, and 286.7 ± 75.8 (mmol/L), respectively, and were higher than those in subjects without NAFLD. The adjusted odds ratios (ORs) with 95% confidence interval (CI) for NAFLD among participants in the menopause transition period and postmenopausal period were 1.10 (0.89-1.37) and 1.28 (1.04-1.58), respectively, compared with the menstrual period women. Compared to the lowest quartile of SUA, the adjusted ORs with 95% CI of the highest quartile for NAFLD were 2.24 (1.69-2.99) for females in the menstrual period, 1.92 (1.10-3.37) for females in the menopause transition period, and 1.47 (1.06-2.03) for females in postmenopause.Menstrual status was significantly correlated with NAFLD. High levels of SUA were associated with NAFLD in females during the three menstrual periods.
Abstract The most optimal management for postoperative locoregional recurrence of oesophageal squamous cell carcinoma is still controversial. Several studies have reported the feasibility and efficacy of concurrent chemoradiotherapy (CCRT), mostly with three-weekly or four-weekly schedule of chemotherapy. However, treatment compliance was not quite satisfactory, probably due to treatment-related toxicities. Since CCRT with weekly chemotherapy regimens have demonstrated a favorable toxicity profile as well as promising survival in certain types of cancer, we aimed to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly chemotherapy with 5-fluorouracil (5-FU) and platinum agents for patients with postoperative locoregional recurrence of oesophageal squamous cell carcinoma in our center. Twenty-seven consecutive patients who were diagnosed with postoperative locoregional recurrence of oesophageal squamous cell carcinoma and received CCRT with weekly chemotherapy of 5-FU and platinum agents were retrospectively analyzed. Our data showed that the present protocol of radiotherapy combined concurrently with weekly chemotherapy of 5-FU and platinum agents was a safe and effective salvage treatment for postoperative locoregional recurrence of oesophageal squamous cell carcinoma.
Defects in O -mannosylation of α-dystroglycan are thought to cause certain types of congenital muscular dystrophies with neuronal migration disorders. Among these muscular dystrophies, Walker–Warburg syndrome is caused by mutations in the gene encoding putative protein O -mannosyltransferase 1 (POMT1), which is homologous to yeast protein O -mannosyltransferases. However, there is no evidence that POMT1 has enzymatic activity. In this study, we first developed a method to detect protein O -mannosyltransferase activity in mammalian cells. Then, using this method, we showed that coexpression of both POMT1 and POMT2 (another gene homologous to yeast protein O -mannosyltransferases) was necessary for the enzyme activity, but expression of either POMT1 or POMT2 alone was insufficient. The requirement of an active enzyme complex of POMT1 and POMT2 suggests that the regulation of protein O -mannosylation is complex. Further, protein O -mannosylation appears to be required for normal structure and function of α-dystroglycan in muscle and brain. In view of the potential importance of this form of glycosylation for a number of developmental and neurobiological processes, the ability to assay mammalian protein O -mannosyltransferase activity should greatly facilitate progress in the identification and localization of O -mannosylated proteins and the elucidation of their functional roles.
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