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Objective: Metabolic disturbances induce endoplasmic reticulum stress (ERS) in pancreatic beta cells. This study aims to investigate whether a common pathway exists in the ERS induced by various chemicals, including high levels of glucose and palmitate in INS-1-3 cells. Method: ERS in INS-1-3 cells was induced by exposure cells to thapsigargin (TG), tunicamycin (TM) or palmitic acid (PA) +high glucose (HG). Digital gene expression (DGE) profiling technique was used to detect differentially expressed genes. The profile of gene expression was detected by gene oncology (GO) function and pathway enrichment analysis. Nkx6.1 over-expression was established in INS-1-3 cell lines by lentivirus infection to revert the inhibition of Nkx6.1 expression found in the situation of ERS. Real time reverse transcription polymerase chain reaction (RT-PCR) was used to verify the expression changes of key genes. Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The apoptosis was determined by flow cytometry. INS-1-3 cell function was measured by glucose stimulated insulin secretion test(GSIS). Results: As compared to control, DGE demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+PA groups, respectively. Those differentially expressed genes were enriched to ERS, antigen processing and presentation, protein export pathways, and interestingly, the maturity onset diabetes of the young (MODY) pathway. Nkx6.1 is one of common down-regulated gene in MODY signaling pathway among TM, TG and HG+PA groups. Over-expression of Nkx6.1 ameliorated glucolipotoxicity induced apoptosis rate by 45.4%, and increased proliferation by 40.9%. At the same time, GSIS increased by 1.82 folds. Conclusions: MODY pathway genes expression was changed in the state of ERS. Over-expression of Nkx6.1 protected the INS-1-3 cells from glucolipotoxicity. [ABSTRACT FROM AUTHOR]

Summary: The cyclin D1 proto-oncoprotein is a crucial regulator in cell-cycle progression, and aberrant overexpression of cyclin D1 is linked to tumorigenesis of many different cancer types. By screening ubiquitinated cyclin D1 as a substrate with a deubiquitinase library, we have identified USP2 as a specific deubiquitinase for cyclin D1. USP2 directly interacts with cyclin D1 and promotes its stabilization by antagonizing ubiquitin-dependent degradation. Conversely, USP2 knockdown destabilizes cyclin D1 and induces growth arrest in the human cancer lines where cell growth is dependent on cyclin D1 expression. Of note, cyclin D1 is not universally required for cell-cycle progression. Inactivation of USP2 has either very mild effects on cell growth in normal human fibroblasts or no effect in the cancer cells that do not express cyclin D1. These findings suggest that targeting USP2 is an effective approach to induce growth suppression in the cancer cells addicted to cyclin D1 expression. [Copyright &y& Elsevier]

Abstract: Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)–AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells. [Copyright &y& Elsevier]

Summary The development of plant virus‐based expression systems has expanded rapidly owing to their potential applications in gene functional and disease resistance research, and industrial production of pharmaceutical proteins. However, the low yield of certain proteins, especially high‐molecular‐mass proteins, restricts the production scale. In this study, we observed that the tobacco mosaic virus (TMV)‐mediated expression of a foreign protein was correlated with the amount of the movement protein (MP) and developed a TMV‐derived pAT‐transMP vector system incorporating trans‐complementation expression of MP. The system is capable of efficient expression of exogenous proteins, in particular those with a high molecular mass, and enables simultaneous expression of two target molecules. Furthermore, viral expression of competent CRISPR‐Cas9 protein and construction of CRISPR‐Cas9‐mediated gene‐editing system in a single pAT‐transMP construct was achieved. The results demonstrated a novel role for TMV‐MP in enhancing the accumulation of a foreign protein produced from the viral vector or a binary expression system. Further investigation of the mechanism underlying this role will be beneficial for optimization of plant viral vectors with broad applications. [ABSTRACT FROM AUTHOR]

Background: Laryngeal squamous cell carcinoma (LSCC) is one of the most prevalent malignant neoplasms of the upper respiratory tract. Studies have confirmed that an unstable chromosome constitution promotes the progress of laryngeal tumorigenesis, and ACYP2 has been confirmed as a telomere length‐related gene. However, to date, the association between ACYP2 polymorphisms and LSCC susceptibility has not been investigated. Methods: We performed this study to explore the effect of 11 single‐nucleotide polymorphisms (SNPs) in ACYP2 on LSCC susceptibility in Chinese Han males. Unconditional logistic regression analysis adjusted for age was used to calculate the odds ratios and 95% confidence intervals. Results: Based on allele and genotype models, our results showed that rs1682111 variant was significantly associated with a decreased LSCC susceptibility (p < 0.05). On the contrary, polymorphisms of rs10439478, rs11125529, rs12615793, rs843711, rs11896604, and rs17045754 were significantly associated with an increased LSCC risk (p < 0.05). The results of haplotype analysis indicated that haplotypes "TTCTCG" and "TTCTAA" in block 1 and "TG" in block 2 showed a risk factor for the development of LCSS (p = 0.009, p < 0.001, and p = 0.001, respectively). The results of Genotype‐Tissue Expression analysis indicate that these significant SNPs were known to be associated with ACYP2 expression. Conclusion: Our data demonstrated that ACYP2 polymorphisms may exert effects on LSCC susceptibility in Chinese Han males. [ABSTRACT FROM AUTHOR]

Summary: The reprogramming factors that induce pluripotency have been identified primarily from embryonic stem cell (ESC)-enriched, pluripotency-associated factors. Here, we report that, during mouse somatic cell reprogramming, pluripotency can be induced with lineage specifiers that are pluripotency rivals to suppress ESC identity, most of which are not enriched in ESCs. We found that OCT4 and SOX2, the core regulators of pluripotency, can be replaced by lineage specifiers that are involved in mesendodermal (ME) specification and in ectodermal (ECT) specification, respectively. OCT4 and its substitutes attenuated the elevated expression of a group of ECT genes, whereas SOX2 and its substitutes curtailed a group of ME genes during reprogramming. Surprisingly, the two counteracting lineage specifiers can synergistically induce pluripotency in the absence of both OCT4 and SOX2. Our study suggests a “seesaw model” in which a balance that is established using pluripotency factors and/or counteracting lineage specifiers can facilitate reprogramming. [ABSTRACT FROM AUTHOR]