The plant gaseous hormone ethylene regulates many aspects of plant growth, development and responses to the environment. ETHYLENE INSENSITIVE3 (EIN3) is a transcription factor involved in the ethylene signal transduction pathway in Arabidopsis. To gain a better understanding of the ethylene signal transduction pathway in rice, six EIN3-like genes (designated OsEIL1-6) were identified. OsEIL1, which showed highest similarity with EIN3, was isolated and functionally characterized. Ectopic expression of OsEIL1 in Arabidopsis can partially complement the ein3-1 mutant. The transgenic rice plants with overexpression of OsEIL1 exhibit short root, coiled primary root and slightly short shoot phenotype and elevated response to exogenous ethylene. OsEBP89, an ethylene responsive element binding protein (EREBP) and OsACO1, an ACC (1-aminocyclopropane-1-carboxylic acid) oxidase gene were enhanced in the OsEIL1 overexpressing transgenic plants. These results indicate that OsEIL1 is involved in ethylene signal transduction pathway and acts as a positive regulator of ethylene response in rice.
Fe(II) and α-ketoglutarate-dependent fat mass and obesity associated protein (FTO)-dependent demethylation of m⁶A is important for regulation of mRNA splicing and adipogenesis. Developing FTO-specific inhibitors can help probe the biology of FTO and unravel novel therapeutic targets for treatment of obesity or obesity-associated diseases. In the present paper, we have identified that 4-chloro-6-(6'-chloro-7'-hydroxy-2',4',4'-trimethyl-chroman-2'-yl)benzene-1,3-diol (CHTB) is an inhibitor of FTO. The crystal structure of CHTB complexed with human FTO reveals that the novel small molecule binds to FTO in a specific manner. The identification of the novel small molecule offers opportunities for further development of more selective and potent FTO inhibitors.
Understanding the molecular mechanism by which epithelial mesenchymal transition (EMT)-mediated cancer metastasis and how microRNA (miRNA) regulates lung cancer progression via Twist1-activated EMT may provide potential therapeutic targets for cancer therapy. Here we found that miR-33a, an intronic miRNA located within the sterol regulatory element-binding protein 2 (SREBP-2) gene, is expressed at low levels in metastatic non-small cell lung cancer (NSCLC) cells and is inversely correlated with Twist1 expression. Conversely, miR-33a knockdown induces EMT and miR-33a overexpression blocks EMT by regulating of Twist1 expression in NSCLC cells. Bioinformatical prediction and luciferase reporter assay confirm that Twist1 is a direct target of miR-33a. Additionally, Twist1 knockdown blocks EMT-related metastasis and forced expression of miR-33a inhibits lung cancer metastasis in a xenograft animal model. Clinically, miR-33a is found to be at low levels in NSCLC patients and down-regulation of miR-33a predicts a poor prognosis. These findings suggest that miR-33a targets Twist1 and inhibits invasion and metastasis in NSCLC. Thus, miR-33a might be a potential prognostic marker and of therapeutic relevance for NSCLC metastasis intervention.
Glycosylation is a posttranslational modification occurring in many secreted and membrane-associated proteins in eukaryotes. It plays important roles in both physiological and pathological processes. Most of these protein modifications depend on UDP-N-acetylglucosamine. In this study, a T-DNA insertional rice (Oryza sativa) mutant exhibiting a temperature-sensitive defect in root elongation was isolated. Genetic and molecular analysis indicated that the mutated phenotype was caused by loss of function of a gene encoding a glucosamine-6-P acetyltransferase (designated OsGNA1), which is involved in de novo UDP-N-acetylglucosamine biosynthesis. The aberrant root morphology of the gna1 mutant includes shortening of roots, disruption of microtubules, and shrinkage of cells in the root elongation zone. Our observations support the idea that protein glycosylation plays a key role in cell metabolism, microtubule stabilization, and cell shape in rice roots.UDP-N-acetylglucosamine (UDP-GlcNAc) is an essential metabolite that plays an important role in protein and lipid glycosylation in eukaryotes. The glycans on cell surface glycoproteins are instrumental for cell-cell or cell-matrix interactions, immune reactions, and tumor development, while sugar modifications on secreted proteins are important for their transport, biological activity, and clearance from circulation (Varki et al., 1999). Asn (N)-linked glycans (N-glycans) are components of most membraneassociated and secreted proteins in eukaryotic cells. N-glycans are assembled by the initial step of the transfer of a synthesized dolichol-linked oligosaccharide precursor en bloc to a nascent polypeptide chain in the endoplasmic reticulum. Maturation of the oligomannose precursor requires the action of glucosidases, mannosidases, and Golgi-resident glycosyltransferases. Synthesis of this oligosaccharide precursor initiates with the donor of UDP-GlcNAc and the enzyme of UDP-GlcNAc: dolichol phosphate GlcNAc-1-P transferase (Lowe and Marth, 2003;Haltiwanger and Lowe, 2004). The other proteins that pass through the secretory apparatus are O-glycan modified by the addition of carbohydrates to the OH group of Ser or Thr. The synthesis of O-glycans is initiated with N-acetylgalactosamine (GalNAc) modification of Ser or Thr and employs sequential addition of monosaccharides. The branch synthesis of many O-glycans requires Golgi-routed UDP-GlcNAc (for review, see Lowe and Marth, 2003).UDP-GlcNAc also involves the generation of glycosylphospatidylinositol linkers for anchoring a variety of cell surface molecules to the plasma membrane. The transfer of GlcNAc from UDP-GlcNAc to phosphatidylinositol is the initial reaction of the glycosylphospatidylinositol assembly (Lowe and Marth, 2003;Haltiwanger and Lowe, 2004). Furthermore, many cytosolic and nuclear proteins, such as transcription factors, nuclear pore proteins, and cytoskeletal components, are O-glycosylated on Ser or Thr with a single GlcNAc residue (O-GlcNAc). This type of modification is reversible. The protein modifica...
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