Neuroblastoma (NB) is a pediatric cancer characterized by remarkable cell heterogeneity within the tumor nodules. Here, we demonstrate that the synthesis of a pol III-transcribed noncoding (nc) RNA (NDM29) strongly restricts NB development by promoting cell differentiation, a drop of malignancy processes, and a dramatic reduction of the tumor initiating cell (TIC) fraction in the NB cell population. Notably, the overexpression of NDM29 also confers to malignant NB cells an unpredicted susceptibility to the effects of antiblastic drugs used in NB therapy. Altogether, these results suggest the induction of NDM29 expression as possible treatment to increase cancer cells vulnerability to therapeutics and the measure of its synthesis in NB explants as prognostic factor of this cancer type.-Castelnuovo, M., Massone, S., Tasso, R., Fiorino, G., Gatti, M., Robello, M., Gatta, E., Berger, A., Strub, K., Florio, T., Dieci, G., Cancedda, R., Pagano, A. An Alu-like RNA promotes cell differentiation and reduces malignancy of human neuroblastoma cells. FASEB J. 24, 000 -000 (2010). www.fasebj.org
Repetitive Alu and Alu-related elements are present in primates, tree shrews (Scandentia), and rodents and have expanded to 1.3 million copies in the human genome by nonautonomous retrotransposition. Pol III transcription from these elements occurs at low levels under normal conditions but increases transiently after stress, indicating a function of Alu RNAs in cellular stress response. Alu RNAs assemble with cellular proteins into ribonucleoprotein complexes and can be processed into the smaller scAlu RNAs. Alu and Alu-related RNAs play a role in regulating transcription and translation. They provide a source for the biogenesis of miRNAs and, embedded into mRNAs, can be targeted by miRNAs. When present as inverted repeats in mRNAs, they become substrates of the editing enzymes, and their modification causes the nuclear retention of these mRNAs. Certain Alu elements evolved into unique transcription units with specific expression profiles producing RNAs with highly specific cellular functions.
This study presents the isolation and characterization of a novel nonsymbiotic Hb gene from sessile oak (Quercus petraea) seedlings, herein designated QpHb1. The cellular and tissue expression of QpHb1 was analysed by Northern blotting and in situ hybridization. The encoded protein was predicted to consist of 161 amino acid residues, and shares 71 and 51% amino acid sequence identity with the Arabidopsis class 1 and 2 nonsymbiotic Hb, respectively. Northern blot analysis revealed that QpHb1 was strongly expressed in roots. Spatial expression analysis of QpHb1 in the root apical region of sessile oak by in situ hybridization indicated that transcripts were mostly abundant in protoxylem cell initials, some cortical cells and the protoderm. In addition, when comparing the expression profile of QpHb1 in sessile and pedunculate oak (Quercus robur), two species with contrasted hypoxia tolerance, the transcript level of QpHb1 rose early in the most flood-tolerant species, pedunculate oak, during root submergence. The spatial-temporal expression of QpHb1 suggests that this gene could participate in perception and signalling during hypoxia.
Stress granules (SGs) are formed in response to stress, contain mRNAs, 40S ribosomal subunits, initiation factors, RNA-binding and signaling proteins, and promote cell survival. Our study describes a novel function of the protein heterodimer SRP9/14 and Alu RNA in SG formation and disassembly. In human cells, SRP9/14 exists assembled into SRP, bound to Alu RNA and as a free protein. SRP9/14, but not SRP, localizes to SGs following arsenite or hippuristanol treatment. Depletion of the protein decreases SG size and the number of SG-positive cells. Localization and function of SRP9/14 in SGs depend primarily on its ability to bind directly to the 40S subunit. Binding of SRP9/14 to 40S and Alu RNA is mutually exclusive indicating that the protein alone is bound to 40S in SGs and that Alu RNA might competitively regulate 40S binding. Indeed, by changing the effective Alu RNA concentration in the cell or by expressing an Alu RNA binding-defective protein we were able to influence SG formation and disassembly. Our findings suggest a model in which SRP9/14 binding to 40S promotes SG formation whereas the increase in cytoplasmic Alu RNA following stress promotes disassembly of SGs by disengaging SRP9/14 from 40S.
The human genome contains about 1.5 million Alu elements, which are transcribed into Alu RNAs by RNA polymerase III. Their expression is upregulated following stress and viral infection, and they associate with the SRP9/14 protein dimer in the cytoplasm forming Alu RNPs. Using cell-free translation, we have previously shown that Alu RNPs inhibit polysome formation. Here, we describe the mechanism of Alu RNP-mediated inhibition of translation initiation and demonstrate its effect on translation of cellular and viral RNAs. Both cap-dependent and IRES-mediated initiation is inhibited. Inhibition involves direct binding of SRP9/14 to 40S ribosomal subunits and requires Alu RNA as an assembly factor but its continuous association with 40S subunits is not required for inhibition. Binding of SRP9/14 to 40S prevents 48S complex formation by interfering with the recruitment of mRNA to 40S subunits. In cells, overexpression of Alu RNA decreases translation of reporter mRNAs and this effect is alleviated with a mutation that reduces its affinity for SRP9/14. Alu RNPs also inhibit the translation of cellular mRNAs resuming translation after stress and of viral mRNAs suggesting a role of Alu RNPs in adapting the translational output in response to stress and viral infection.
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