Estrogen stimulates cell growth and inhibits apoptosis through estrogen receptor-mediated mechanisms in many cell types. Remarkably, there is another dimension to estrogen action by which apoptosis ...is induced in breast cancer cells. While these mechanisms are not yet completely understood, finding the molecules involved has paved the way for the development of a new drug group. Using ChIP-chip, we have demonstrated that Klf10, a Krüppel-like zinc finger transcription factor, which was induced in response to estrogen, directly modulates the transcription of BI-1 (Bax inhibitor-1; also called the testis-enhanced gene transcript, TEGT). Eventually, the estrogen induced Klf10 and then suppresses BI-1 transcription. The estrogen/Klf10/BI-1 interrelationship was further confirmed using BI-1 promoter and EMSA assays. The estrogen-elicited reduction of BI-1 promoter activity was significantly reversed when the Klf10 binding element was mutated to abolish Klf10 binding. A si-Klf10 antisense-oligo nucleotide was also able to restore BI-1 promoter activity to its pre-estrogen-treatment level. BI-1 is known to regulate stress via the endoplasmic reticulum; in this context down-regulation of BI-1 is able to cause Ca²⁺ release and trigger an apoptosis pathway in breast cancer. In our study, Klf10 not only suppressed cellular BI-1 expression but also increased the cytosolic Ca²⁺ concentration, eventually causing apoptotic cell death. Based on these results, we suggest the pathway by which estrogen induces apoptosis is possibly through an up-regulation of Klf10 that decreases BI-1 and finally increases the concentration of cytoplasmic calcium.
KLF10 is a transforming growth factor (TGF)-β/Smad downstream regulated gene. KLF10 binds to the promoter of target genes and mimics the effects of TGF-β as a transcriptional factor. In our ...laboratory, we noted that Klf10 deficiency in mice is associated with significant inflammation of the lungs. However, the precise mechanism of this association remains unknown. We previously identified NPRA as a target gene potentially regulated by KLF10 through direct binding; NPRA knockout have known that prevented lung inflammation in a mouse model of allergic asthma. Here, we further explored the regulatory association between KLF10 and NPRA on the basis of the aforementioned findings. Our results demonstrated that KLF10 acts as a transcriptional repressor of NPRA and that KLF10 binding reduces NPRA expression in vitro. Compared with wild-type mice, Klf10-deficient mice were more sensitive to lipopolysaccharide or ovalbumin challenge and showed more severe inflammatory histological changes in the lungs. Moreover, Klf10-deficient mice showed pulmonary neutrophil accumulation. These findings collectively reveal the precise site where KLF10 signaling affects pulmonary inflammation by attenuating NPRA expression. They also verify the importance of KLF10 and atrial natriuretic peptide/NPRA in exerting influences on chronic pulmonary disease pathogenesis.
Downregulation of multiple cell cycle-regulatory molecules is a dominant event in TGF-β1-mediated growth inhibition of human carcinoma cells. It is known that KLF10 mimics the anti-proliferative and ...apoptotic effects that TGF-β1 has on epithelial cell growth and the growth of various tumor cells; based on these findings it is considered as a tumor suppressor. KLF10 protein expression is tightly associated with cell cycle-dependent events. However, the regulatory mechanism and its biological meaning have not been identified. In this study, we have demonstrated that KLF10 is a substrate of CDK2/cyclin E and can be phosphorylated. We also have shown that KLF10 efficiently binds to CDK2, while binding much less to CDK4, and displaying no binding to Cdk6. Using mass spectrometry, site direct mutagenesis, in vitro kinase assays and depletion assays, we have established that CDK2 phosphorylates Ser206, which subsequently affects the steady state level of KLF10 in cells. Our studies have also proved that CDK2 up-regulates the protein level of KLF10 through reducing its association with SIAH1, a KLF10 E3-ubiqutin ligase involved in proteasomal degradation. Taken all together, these findings indicate that CDK2-dependent phosphorylation regulates KLF10 stability and that this affects the role of KLF10 in cell.
•KLF10 protein expression was identified associating with cell cycle events.•CDK2 could phosphorylate the KLF10 at Ser206.•Phosphorylated KLF10 presents increasing protein stability and effects in cells.•CDK2 phosphorylation decreases the KLF10 E3-ubiqutin ligase, SIAH1, association.
Located at the low-lying deltaic floodplain of Ganges–Brahmaputra–Meghna river basin, Bangladesh suffers damages from flooding with regularity. From the perspective of long-term planning and ...management, a reliable flood damage function is a critical component in the estimation of flood-induced economic loss. Such functions are, however, notoriously difficult to develop. This study utilizes in-stream water level and flood-affected area (FAA) data from Flood Forecasting and Warning Center and Bangladesh Water Development Board to evaluate the best form and data input characteristics of flood damage functions for Bangladesh. The performance of various function configurations (geographic data, water level data, and function form) was tested. The Nash–Sutcliffe efficiency and residual error analysis results suggest that, in general, the logistic function performs better than the other two function forms, and the maximum of daily-maximal water level is the best suited to estimate (FAA). As expected, when information is available from all basins (the Ganges, the Brahmaputra, and the Meghna), the resulting flood damage functions provide the most accurate estimations of FAA. Furthermore, the comparison between single- and multivariable flood damage functions does not demonstrate a clear advantage of using multivariate function in our study area. When flood damage functions with finer spatial and temporal resolution can be constructed using remote sensing technology or hydrodynamic modeling, the intra-year and district-level changes to FAA can be evaluated. These findings provide a better flood management plan for Bangladesh and have potential to be generalized to other similarly flood-affected nations.
Although arsenic contaminated groundwater in Bangladesh is a serious health issue, little is known about the complex transient patterns of groundwater flow that flush solutes from aquifers and carry ...solutes into the subsurface. Hydrologic modeling results for our field site in the Munshiganj district indicate that groundwater flow is vigorous, flushing the aquifer over time-scales of decades to a century, and also transporting solute loads into the aquifer with recharge from ponds, rivers and rice fields. The combined hydrologic and biogeochemical results from our field site imply that the biogeochemistry of the aquifer system may not be in steady-state, and that the net effect of competing processes could either increase or decrease arsenic concentrations over the next decades. Modeling results suggest that irrigation has greatly changed the location, timing and chemical content of recharge to the aquifer, flushing water through the system more quickly, and also cycling large fluxes of water through rice fields during the dry season that could mobilize arsenic from oxides in near-surface sediments. Furthermore, the hydrologic model reveals that ponds, many of which have been excavated over the last 50 years, now provide much of the groundwater recharge. These ponds receive most of the waste from the villages and thus provide another potential source of organic carbon to the groundwater system.
Abstract Background and purpose Krüpple-like factor 10 (Klf10), an early response gene of TGFβ, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in ...predicting tumor response to cancer treatment is unknown. Materials and methods Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay. Orthotopic murine tumor model and clinical specimens were used to evaluate radio-sensitivity of pancreatic cancer. Results We found Klf10 silencing correlates with enhanced pancreatic cancer clonogenic survival and murine tumor growth after radiation. UVRAG was an essential down-stream mediator transcriptionally suppressed by Klf10. Silencing UVRAG mRNA in Klf10 depleted Panc-1 cells reversed the radio-resistant phenotypes including decreased apoptosis and enhanced DNA repair as well as autophagy. Metformin, an anti-diabetic agent, was found to increase Klf10 and suppress UVRAG expression to improve radiation cytotoxicity in pancreatic cancer. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients. Conclusions Klf10 is a potential biomarker in predicting and sensitizing radiation effect in pancreatic cancer.
Arsenic Mobility and Groundwater Extraction in Bangladesh Harvey, Charles F.; Swartz, Christopher H.; Badruzzaman, A. B. M. ...
Science (American Association for the Advancement of Science),
11/2002, Letnik:
298, Številka:
5598
Journal Article
Recenzirano
High levels of arsenic in well water are causing widespread poisoning in Bangladesh. In a typical aquifer in southern Bangladesh, chemical data imply that arsenic mobilization is associated with ...recent inflow of carbon. High concentrations of radiocarbon-young methane indicate that young carbon has driven recent biogeochemical processes, and irrigation pumping is sufficient to have drawn water to the depth where dissolved arsenic is at a maximum. The results of field injection of molasses, nitrate, and low-arsenic water show that organic carbon or its degradation products may quickly mobilize arsenic, oxidants may lower arsenic concentrations, and sorption of arsenic is limited by saturation of aquifer materials.
Climate change assessments often inadequately address uncertainty when estimating damages. Using a dynamic economy‐wide model of Bangladesh, damages from historical climate variability and future ...anthropogenic climate change are estimated and decomposed. The stochastic simulation approach used avoids biases caused by non‐linear damage functions and fixed occurrences of extreme events in historical data. Using 10 climate projections, it is found that future anthropogenic climate change damages until 2050 are, on average, one‐fifth of those from historical climate variability. Climate change also alters the temporal distribution of damages and slows Bangladesh's long run shift (adaptation) into dry (winter) season rice production.
The human papillomavirus (HPV) oncoprotein E7 is a major transforming protein. The E7 protein does not possess intrinsic enzymatic activity, but rather functions through direct and indirect ...interactions with cellular proteins, several of which are well known cellular tumor suppressors. Using the yeast two-hybrid system, we found that transforming growth factor-beta inducible early gene 1 (TIEG1), a member of the Krüppel-like family (KLF) that has been implicated as a putative tumor suppressor, interacts and forms a specific complex with HPV-16 E7. TIEG1 has been shown to mimic the effects of TGF-beta in various carcinoma cells and plays a critical role in the apoptotic cascade. Our results indicate that E7 binds to the C-terminus of TIEG1 and induces its degradation via the ubiquitin pathway. E7 not only increased the ubiquitination of TIEG1 but also influenced the ability of TIEG1 to affect apoptosis. Our results suggest that suppression of TIEG1-mediated signaling by E7 may contribute to HPV-associated carcinogenesis.
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