SUMMARY Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
Activation of oncogenes underlies the pathogenesis of most human cancers. In neuroblastoma, amplification of the oncogene MYCN occurs in ϳ22% of cases and is associated with advanced stages of the disease and poor prognosis. Identification of other oncogenes that are consistently mutated or overexpressed in neuroblastoma is crucial for a molecular understanding of the pathogenic process. Here, we report that the oncogene Bmi-1 is highly expressed in human neuroblastoma cell lines and primary tumors. Neuroblastoma development in MYCN transgenic mice, an animal model for the human disease, was associated with a marked increase in the levels of Bmi-1 expression. Bmi-1 cooperated with MYCN in transformation of benign S-type neuroblastoma cells and avian neural crest cells by inhibiting the apoptotic activity of MYCN. Importantly, down-regulation of Bmi-1 impaired the ability of neuroblastoma cells to grow in soft agar and induce tumors in immunodeficient mice. Moreover, Bmi-1-knockdown neuroblastoma xenografts were characterized by a significant increase in the amount of Schwannian stroma, a histological feature associated with clinically favorable neuroblastomas. These findings suggest a crucial role for Bmi-1 in neuroblastoma pathogenesis and provide insights into the molecular basis of neuroblastoma heterogeneity.
Establishing the architecture of the gene regulatory networks (GRNs) responsible for controlling the transcription of all genes in an organism is a natural development that follows elucidation of the genome sequence. Reconstruction of the GRN requires the availability of a series of molecular tools and resources that so far have been limited to a few model organisms. One such resource consists of collections of transcription factor (TF) open reading frames (ORFs) cloned into vectors that facilitate easy expression in plants or microorganisms. In this study, we describe the development of a publicly available maize TF ORF collection (TFome) of 2034 clones corresponding to 2017 unique gene models in recombination-ready vectors that make possible the facile mobilization of the TF sequences into a number of different expression vectors. The collection also includes several hundred co-regulators (CoREGs), which we classified into well-defined families, and for which we propose here a standard nomenclature, as we have previously done for TFs. We describe the strategies employed to overcome the limitations associated with cloning ORFs from a genome that remains incompletely annotated, with a partial full-length cDNA set available, and with many TF/CoREG genes lacking experimental support. In many instances this required the combination of genome-wide expression data with gene synthesis approaches. The strategies developed will be valuable for developing similar resources for other agriculturally important plants. Information on all the clones generated is available through the GRASSIUS knowledgebase (http://grassius.org/).
NADPH oxidases (NOXs), mostly known as respiratory burst oxidase homologs (RBOHs), are the key producers of reactive oxygen species (ROS) in plants. A lot of literature has addressed ROS signaling in plant development regulation and stress responses as well as on the enzyme’s structure, evolution, function, regulation and associated mechanisms, manifesting the role of NOXs/RBOHs as the vital performers and center hubs during plant growth and signaling. This review focuses on recent advances of NOXs/RBOHs on cell growth, hormone interaction, calcium signaling, abiotic stress responses, and immunity. Several primary particles, including Ca2+, CDPKs, BIK1, ROPs/RACs, CERK, FER, ANX, SnRK and SIK1-mediated regulatory mechanisms, are fully summarized to illustrate the signaling behavior of NOXs/RBOHs and their sophisticated and dexterous crosstalks. Diverse expression and activation regulation models endow NOXs/RBOHs powerful and versatile functions in plants to maintain innate immune homeostasis and development integrity. NOXs/RBOHs and their related regulatory items are the ideal targets for crop improvement in both yield and quality during agricultural practices.
With the growth of the global population and uncontrollable natural disasters, crop yields must be steadily increased to enhance human adaptability to risks. Pre-harvest sprouting (PHS) is a global disaster for agricultural production, which is mainly used to describe the phenomenon in which grains germinate on the mother plant directly before harvest. After domestication, the dormancy level of cultivated crops was generally lower than that of wild ancestors. Although the shortened dormancy period likely improved the industrial performance of cereals such as wheat, barley, rice, and maize, the excessively high germination rate has caused frequent PHS in areas with higher rainfall, causing great economic losses. Here, we systematically reviewed the causes and harms of PHS, the major indicators and methods for PHS assessment, emphasising the biological significance of PHS in crop production. Wheat quantitative trait loci (QTLs) functioning in PHS controls were also comprehensively summarised for a meta-analysis. Finally, we used Arabidopsis as a model plant to develop more complete PHS regulatory networks for wheat. The integration of this information is conducive to cultivating custom-made cultivated lines suitable for different demands and different regions and is of great significance for improving crop yield and economic benefits.
The NF-B2 gene is recurrently mutated in human lymphoid malignancies. However, a causal relationship between NF-B2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. We report the generation of transgenic mice with targeted expression of p80HT, a lymphoma-associated NF-B2 mutant, in lymphocytes. The transgenic mice display a marked expansion of peripheral B cell populations and develop predominantly small B cell lymphomas. p80HT expression has no apparent effect on the proliferation of B cells, but renders them specifically resistant to apoptosis induced by cytokine deprivation and mitogenic stimulation. Lymphocytes and lymphoma cells from p80HT mice express high levels of TRAF1, an antiapoptotic protein also implicated in lymphoid malignancies. p80HT binds the TRAF1 promoter in vivo and activates TRAF1 transcription. Moreover, TRAF1 knockdown abrogates the antiapoptotic activity of p80HT and TRAF1 deficiency reestablishes B cell homeostasis in p80HT mice. These findings demonstrate NF-B2 mutation as an oncogenic event in vivo and suggest a molecular pathway for TRAF1 activation in the pathogenesis of lymphomas. ( IntroductionThe mammalian NF-B family consists of 5 structurally related proteins, including RelA, RelB, c-Rel, NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100). The active forms of NF-B are dimers composed of various combinations of the family members, which bind a common DNA sequence motif known as the B site and regulate the expression of genes crucial to the development and functions of lymphocytes. NF-B activity is controlled by IB (inhibitor of B) proteins and the IB-like ankyrin-repeat domain in the C-terminal region of NF-B2 p100. IB proteins interact with NF-B dimers composed of NF-B1 p50 and RelA or c-Rel, and NF-B2 p100 is primarily associated with RelB. The interactions prevent NF-B dimers from translocating to the nucleus. On stimulation by certain cytokines, IBs and the C-terminal region of p100 are phosphorylated by IB kinase and degraded by the proteasome. The freed p50-RelA/c-Rel or resulting p52-RelB dimers then translocate to the nucleus and transactivate their target genes. 1 Constitutive NF-B activation plays an important role in tumorigenesis by promoting cell proliferation and survival. Several mechanisms have been identified by which activation of NF-B is uncoupled from its normal modes of regulation in cancer cells. Most of these mechanisms target IB kinase for activation of NF-B. 2,3 Sustained NF-B activation can also be caused by genetic alterations that affect the activity and expression of NF-B proteins. 4 The first gene of the family found to be mutated in human lymphoid malignancies is NF-B2. 5 Subsequent studies revealed that chromosomal rearrangements at the NF-B2 locus occur in a variety of B and T cell lymphoid malignancies. [6][7][8][9] A cardinal feature of these genetic alterations is the generation of C-terminally truncated NF-B2 mutants that lack various portions...
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