Akbari O.S.,California Institute of Technology |
Chen C.-H.,Institute of Molecular and Genomic Medicine |
Marshall J.M.,Imperial College London |
Huang H.,California Institute of Technology |
And 2 more authors.
ACS Synthetic Biology | Year: 2014
Insects act as vectors for diseases of plants, animals, and humans. Replacement of wild insect populations with genetically modified individuals unable to transmit disease provides a potentially self-perpetuating method of disease prevention. Population replacement requires a gene drive mechanism in order to spread linked genes mediating disease refractoriness through wild populations. We previously reported the creation of synthetic Medea selfish genetic elements able to drive population replacement in Drosophila. These elements use microRNA-mediated silencing of myd88, a maternally expressed gene required for embryonic dorso-ventral pattern formation, coupled with early zygotic expression of a rescuing transgene, to bring about gene drive. Medea elements that work through additional mechanisms are needed in order to be able to carry out cycles of population replacement and/or remove existing transgenes from the population, using second-generation elements that spread while driving first-generation elements out of the population. Here we report the synthesis and population genetic behavior of two new synthetic Medea elements that drive population replacement through manipulation of signaling pathways involved in cellular blastoderm formation or Notch signaling, demonstrating that in Drosophila Medea elements can be generated through manipulation of diverse signaling pathways. We also describe the mRNA and small RNA changes in ovaries and early embryos associated from Medea-bearing females. Finally, we use modeling to illustrate how Medea elements carrying genes that result in diapause-dependent female lethality could be used to bring about population suppression. © 2012 American Chemical Society. Source
Tang H.-W.,Academia Sinica, Taiwan |
Tang H.-W.,National Taiwan University |
Liao H.-M.,Academia Sinica, Taiwan |
Liao H.-M.,National Taiwan University |
And 5 more authors.
Developmental Cell | Year: 2013
Autophagy is a highly conserved catabolic process that degrades and recycles intracellular components through the lysosomes. Atg9 is the only integral membrane protein among autophagy-related (Atg) proteins thought to carry the membrane source forforming autophagosomes. Here we show that Drosophila Atg9 interacts with Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2) to regulate the c-Jun N-terminal kinase (JNK) signaling pathway. Significantly, depletion of Atg9 and dTRAF2 compromised JNK-mediated intestinal stem cell proliferation and autophagy induction upon bacterial infection and oxidative stress stimulation. In mammalian cells, mAtg9 interacts with TRAF6, the homolog of dTRAF2, and plays an essential role in regulating oxidative stress-induced JNK activation. Moreover, we found that ROS-induced autophagy acts as a negative feedback regulator of JNK activity by dissociating Atg9/mAtg9 from dTRAF2/TRAF6 in Drosophila and mammalian cells, respectively. Our findings indicate a dual role for Atg9 in the regulation of JNK signaling and autophagy under oxidative stress conditions. © 2013 Elsevier Inc. Source
Fang W.-T.,National Health Research Institute |
Fan C.-C.,Mackay Memorial Hospital |
Fan C.-C.,Yuanpei University |
Li S.-M.,National Health Research Institute |
And 24 more authors.
International Journal of Cancer | Year: 2014
SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells. © 2014 UICC. Source
Huang T.-W.,Institute of Molecular and Genomic Medicine |
Wang J.-T.,National Institute of Infectious Diseases and Vaccinology |
Lauderdale T.-L.,National Health Research Institute |
Liao T.-L.,Institute of Molecular and Genomic Medicine |
And 8 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013
Genetic determinants of a blaNDM-1-positive, multidrug-resistant bacterial isolate that caused active infection was investigated by DNA sequencing. Two plasmids, pKOX-NDM1 and pKOX-R1, were identified for the Klebsiella oxytoca strain E718. Sequence annotation revealed a blaNDM-1 gene in pKOX-NDM1 and two extended-spectrum-lactamase producers (blaCTX-M-3 and blaSHV-12) and a wide array of resistance genes in pKOX-R1. These findings highlight the difficulty in treating multidrugresistant bacterial infections and the potential danger of emerging resistant enterobacteria. Copyright © 2013, American Society for Microbiology. All Rights Reserved. Source