CCAAT/Enhancer Binding Protein-delta (C/EBP-delta) regulates cell growth, migration and differentiation

<p>Abstract</p> <p>Background</p> <p>CCAAT/enhancer binding protein-delta (C/EBP-delta) is a member of the highly conserved C/EBP family of basic region leucine zipper transcription factors. C/EBP family members regulate cell growth and differentiation and "loss of function" alterations in C/EBPs have been reported in a variety of human cancers. C/EBP-delta gene expression is upregulated by G₀growth arrest, IL-6 family cytokines and endotoxin treatments. C/EBP-delta exhibits properties of a tumor suppressor gene, including reduced expression and promoter methylation-induced silencing in transformed cell lines and primary tumors. In addition, C/EBP-delta gene expression is repressed by c-Myc, an oncogene that is over-expressed in a wide range of human cancers. "ChIP-chip" studies demonstrated that C/EBP-delta functions as a transcriptional activator of target genes that function in intracellular signal transduction, transcription, DNA binding/repair, cell cycle control, cell adhesion, and apoptosis. Despite progress in determining the biochemical functions of C/EBP-delta, the specific cellular defects that are induced by C/EBP-delta "loss of function" alterations are poorly understood. This study investigated the impact of C/EBP-delta "loss of function" alterations on growth arrest, migration/invasion and differentiation in nontransformed mouse mammary epithelial cells (MECs) and primary mouse embryo fibroblasts (MEFs).</p> <p>Results</p> <p>C/EBP-delta siRNA transfected MECs exhibited ~90% reduction in C/EBP-delta mRNA and protein levels. C/EBP-delta siRNA treatment resulted in defective growth arrest as demonstrated by persistently elevated BrdU labeling, ³H-thymidine incorporation and cyclin D1 levels in response to growth arrest treatments. C/EBP-delta siRNA treatment also resulted in increased migration/invasion and defective differentiation. C/EBP-delta knockout MEFs exhibited defective growth arrest and increased proliferation/migration. Re-introduction of C/EBP-delta expression restored the growth arrest response of C/EBP-delta knockout MEFs. Finally, deletion of the C/EBP-delta DNA binding domain or the C/EBP-delta bZIP domain resulted in the loss of C/EBP-delta growth inhibition in clonogenic assays.</p> <p>Conclusions</p> <p>This study demonstrates that C/EBP-delta functions in the regulation of critical cell fate determining programs such as growth arrest, migration, and differentiation. These results support the tumor suppressor function of C/EBP-delta and identify potential mechanisms in which "loss of function" alterations in C/EBP-delta could promote cell transformation and tumorigenesis.</p

Myc interacts with Max and Miz1 to repress C/EBPδ promoter activity and gene expression

<p>Abstract</p> <p>Background</p> <p>"Loss of function" alterations in CCAAT/Enhancer Binding Proteinδ (C/EBPδ) have been reported in a number of human cancers including breast, prostate and cervical cancer, hepatocellular carcinoma and acute myeloid leukemia. C/EBPδ gene transcription is induced during cellular quiescence and repressed during active cell cycle progression. C/EBPδ exhibits tumor suppressor gene properties including reduced expression in cancer cell lines and tumors and promoter methylation silencing.</p> <p>We previously reported that C/EBPδ expression is inversely correlated with c-Myc (Myc) expression. Aberrant Myc expression is common in cancer and transcriptional repression is a major mechanism of Myc oncogenesis. A number of tumor suppressor genes are targets of Myc transcriptional repression including C/EBPα, p15^{<it>INK</it>4}, p21^{<it>CIP</it>1}, p27^{<it>KIP</it>1}and p57^{<it>KIP</it>2}. This study investigated the mechanisms underlying Myc repression of C/EBPδ expression.</p> <p>Results</p> <p>Myc represses C/EBPδ promoter activity in nontransformed mammary epithelial cells in a dose-dependent manner that requires Myc Box II, Basic Region and HLH/LZ domains. Chromatin Immunoprecipitation (ChIP) assays demonstrate that Myc, Miz1 and Max are associated with the C/EBPδ promoter in proliferating cells, when C/EBPδ expression is repressed. EMSAs demonstrate that Miz1 binds to a 30 bp region (-100 to -70) of the C/EBPδ promoter which contains a putative transcription initiator (Inr) element. Miz1 functions exclusively as a repressor of C/EBPδ promoter activity. Miz1 siRNA expression or expression of a Miz1 binding deficient Myc (MycV394D) construct reduces Myc repression of C/EBPδ promoter activity. Max siRNA expression, or expression of a Myc construct lacking the HLH/LZ (Max interacting) region, also reduces Myc repression of C/EBPδ promoter activity. Miz1 and Max siRNA treatments attenuate Myc repression of endogenous C/EBPδ expression. Myc Box II interacting proteins RuvBl1 (Pontin, TIP49) and RuvBl2 (Reptin, TIP48) enhances Myc repression of C/EBPδ promoter activity.</p> <p>Conclusion</p> <p>Myc represses C/EBPδ expression by associating with the C/EBPδ proximal promoter as a transient component of a repressive complex that includes Max and Miz1. RuvBl1 and RuvBl2 enhance Myc repression of C/EBPδ promoter activity. These results identify protein interactions that mediate Myc repression of C/EBPδ, and possibly other tumor suppressor genes, and suggest new therapeutic targets to block Myc transcriptional repression and oncogenic function.</p

Long-term temperature records following the M[subscript w] 7.9 Wenchuan (China) earthquake are consistent with low friction

Knowledge of the shear stress on a fault during slip is necessary for a physically-based understanding of earthquakes. Borehole temperature measurements inside the fault zone immediately after an earthquake can record the energy dissipated by this stress. In the first Wenchuan Earthquake Fault Zone Scientific Drilling Project hole (Sichuan province, China) we repeatedly measured temperature profiles from 1.3 to 5.3 yr after the 12 May 2008, M[subscript w] 7.9 Wenchuan earthquake. The previously identified candidate for the principal slip surface had only a small local temperature increase of at most 0.02°C with no obvious decay. The small amplitude of the temperature increase provides an upper bound for the frictional heat–generated coseismic slip, but is unlikely to be a frictionally generated signal. Two larger temperature anomalies are located above and within the fault zone. However, neither anomaly evolves as expected from a frictional transient. We conclude that the frictional heat from the Wenchuan earthquake remains elusive and the total heat generated at this location is much less than 29 MJ/m². Low friction during slip is consistent with the temperature data

Response Prediction of Asphalt Pavement in Cold Region with Thermo-Hydro-Mechanical Coupling Simulation

Although the theoretical pavement structure design method (TPSDM) is widely used for designing asphalt pavements in Japan, it still exhibits certain limitations, such as not considering the variation in moduli of the base and subgrade layers due to water contents, freeze–thaw action, and stress states. This study aims to enhance Japanese TPSDM’s accuracy by considering variations in the resilient modulus of environmental impacts, pavement materials, pavement structure, and traffic load actions to accurately calculate the mechanical responses and predict pavement fatigue life. Firstly, the study develops a 3D Thermo-Hydro-Mechanical (THM) model using the finite element method (FEM) to investigate temperature and moisture distributions of the pavement with time. Then, based on the numerical results of the moisture, temperature, and stress state obtained from the THM analysis, the constant resilient modulus of the base and subgrade layers in the Japanese TPSDM is replaced with a resilient modulus that considers the stress state and the combined effects of water content fluctuations and freeze–thaw action. Finally, the fatigue life of the pavement is calculated based on the obtained mechanical response in THM analysis. The reliability and validity of the proposed fatigue life prediction method are well verified by comparing the calculated with the actual pavement fatigue life. Results indicate that the modifications improve the Japanese TPSDM by considering the environmental impacts, traffic load actions, pavement materials, and pavement structure, thereby improving the accuracy of predicting the fatigue life of asphalt pavements, particularly in cold regions

Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome

In recent years, many natural foods and herbs rich in phytochemicals have been proposed as health supplements for patients with metabolic syndrome (MetS). Theaflavins (TFs) are a polyphenol hydroxyl substance with the structure of diphenol ketone, and they have the potential to prevent and treat a wide range of MetS. However, the stability and bioavailability of TFs are poor. TFs have the marvelous ability to alleviate MetS through antiobesity and lipid-lowering (AMPK-FoxO3A-MnSOD, PPAR, AMPK, PI3K/Akt), hypoglycemic (IRS-1/Akt/GLUT4, Ca2+/CaMKK2-AMPK, SGLT1), and uric-acid-lowering (XO, GLUT9, OAT) effects, and the modulation of the gut microbiota (increasing beneficial gut microbiota such as Akkermansia and Prevotella). This paper summarizes and updates the bioavailability of TFs, and the available signaling pathways and molecular evidence on the functionalities of TFs against metabolic abnormalities in vitro and in vivo, representing a promising opportunity to prevent MetS in the future with the utilization of TFs

Improved utilization of photogenerated charge using fluorine-doped TiO2 hollow spheres scattering layer in dye-sensitized solar cells

We demonstrate a strategy to improve utilization of photogenerated charge in dye-sensitized solar cells (DSSCs) with fluorine-doped TiO2 hollow spheres as the scattering layer, which improves the fill factor from 69.4% to 74.1% and in turn results in an overall efficiency of photoanode increased by 13% (from 5.62% to 6.31%) in comparison with the control device using undoped TiO2 hollow spheres. It is proposed that the fluorine-doping improves the charge transfer and inhibition of charge recombination to enhance the utilization of the photogenerated charge in the photoanode