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

Social Media Promotion: Likers vs. Doubters?

The social media has emerged as an appealing new channel for firms to promote prod- ucts/services. A fundamental but largely unanswered question is how would the firm use social media to promote products. We address the question by focusing on the movie in- dustry and developing a dynamic game-theoretic model. We assume that: 1) firm intends to build its market reputation; 2) consumers always prefer to watch a high-quality movie. Our model suggests that, it can be optimal for a rational firm to underrate the movie. More specifically, we find that the movie distribution firm would have incentives to overrate the movie even if they observe that the movie quality is low. Furthermore, we show that as long as there is a properly designed uncertainty resolution mechanism, the adoption of social media could alleviate the “Lemon” problem in the movie market, which in turn, improves market efficiency

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

A Novel Neural-symbolic System under Statistical Relational Learning

A key objective in field of artificial intelligence is to develop cognitive models that can exhibit human-like intellectual capabilities. One promising approach to achieving this is through neural-symbolic systems, which combine the strengths of deep learning and symbolic reasoning. However, current approaches in this area have been limited in their combining way, generalization and interpretability. To address these limitations, we propose a general bi-level probabilistic graphical reasoning framework called GBPGR. This framework leverages statistical relational learning to effectively integrate deep learning models and symbolic reasoning in a mutually beneficial manner. In GBPGR, the results of symbolic reasoning are utilized to refine and correct the predictions made by the deep learning models. At the same time, the deep learning models assist in enhancing the efficiency of the symbolic reasoning process. Through extensive experiments, we demonstrate that our approach achieves high performance and exhibits effective generalization in both transductive and inductive tasks