Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5) (original) (raw)
Related papers
2011
Non-coding RNA GAS5 (growth arrest-specific transcript 5) is a 5 -TOP (5 -terminal oligopyrimidine tract) RNA, whose translation, and consequently also stability, is controlled by the mTOR (mammalian target of rapamycin) pathway. GAS5 was identified by functional expression cloning and is necessary and sufficient for normal growth arrest in both leukaemic and untransformed human T-lymphocytes. GAS5 is also required for the inhibitory effects of rapamycin and its analogues on T-cells. The striking functional effects of GAS5 may be mediated through the snoRNAs (small nucleolar RNAs) encoded in its introns and/or through the unusual folding of the mRNA itself, which sequesters, and therefore inhibits, the glucocorticoid receptor.
Molecular pharmacology, 2010
The central importance of the serine/threonine protein kinase mTOR (mammalian Target of Rapamycin) in the control of cell growth and proliferation is well established. However, our knowledge both of the upstream pathways controlling mTOR activity and of the downstream events mediating these effects is still seriously incomplete. We report a previously unsuspected role for the nonprotein-coding RNA GAS5 in the inhibition of T-cell proliferation produced by mTOR antagonists such as rapamycin. GAS5 transcripts are up-regulated during growth arrest and after rapamycin treatment, and GAS5 has recently been shown to be necessary and sufficient for normal T-cell growth arrest. Down-regulation of GAS5 using RNA interference protects both leukemic and primary human T cells from the inhibition of proliferation produced by mTOR antagonists. The GAS5 transcript is a member of the 5' terminal oligopyrimidine class of RNAs, which is specifically controlled at the level of translation by the m...
Journal of Medical Biochemistry, 2018
SummaryBackgroundLong non-coding RNA growth arrest-specific 5 (GAS5) is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally,GAS5interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysingGAS5expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response.MethodsGAS5 expression was measured in peripheral blood mononuclear cells taken from 29 childhood ALL patients at diagnosis, on day 15 and day 33 of remission induction therapy using RT-qPCR methodology.ResultsOur results have shown interindividual differences inGAS5expression at all time points. For each ALL patient,GAS5expression was higher on day 15 in comparison to its level at diagnosis (p<0.0005). On day 33, the level ofGAS5expression decreased in comparison with day 1...
Regulation of activation-induced cell death of mature T-lymphocyte populations
Cell and Tissue Research, 2000
Resting mature T lymphocytes are activated when triggered via their antigen-specific T-cell receptor (TCR) to elicit an appropriate immune response. In contrast, preactivated T cells may undergo activation-induced cell death (AICD) in response to the same signals. Along with cell death induced by growth factor deprivation, AICD followed by the elimination of useless or potentially harmful cells preserves homeostasis, leads to the termination of cellular immune responses and ensures peripheral tolerance. T-cell apoptosis and AICD are controlled by survival cytokines such as interleukin-2 (IL-2) and by death factors such as tumor necrosis factor (TNF) and CD95 ligand (CD95L). In AICD-sensitive T cells, stimulation upregulates expression of one or several death factors, which in turn engage specific death receptors on the same or a neighboring cell. Death receptors are activated by oligomerization to rapidly assemble a number of adapter proteins and enzymes to result in an irreversible activation of proteases and nucleases that culminates in cell death by apoptosis. Increased knowledge of the molecular mechanisms that regulate AICD of lymphocytes opens new immunotherapeutic perspectives for the treatment of certain autoimmune diseases, and has implications in other areas such as transplantation medicine and AIDS research.
2005
This PhD thesis aims to examine the growth of T cells in response to cytokines of the common gamma chain (yc) family, in particular interleukin (IL)-2 and IL- 15. Cell growth is commonly used to describe cells in exponential division however the growth of a cell is defined by its size and volume, which is directly related to the rate of cell metabolism and protein synthesis. Naive T cells are small and circulate around the body maintaining a minimal rate of metabolic activity and protein synthesis. During an immune response naive T cells undergo rapid proliferation and differentiate into effector cells. These cells produce and secrete large amounts of cytokines and effector molecules allowing them to mediate their immune function. The differentiation of antigen activated T cells to mature effectors takes several days and is regulated by cytokines. These cytokines need to maintain high rates of cell metabolism for a prolonged period. Thus the cytokines that regulate proliferation and...
Coordinate stabilization of growth-regulatory transcripts in T cell malignancies
Genomics, 2005
We used microarray technology to compare mRNA decay rates of approximately 7000 transcripts in normal purified human T lymphocytes or the malignant T cell lines Jurkat and H9 following transcriptional arrest with actinomycin D. We found that over 2000 transcripts were expressed at abnormal levels in malignant T cells, including approximately 100 transcripts that were overexpressed and exhibited abnormally stable mRNA. Seventeen transcripts that encoded components of the ubiquitin -proteasome system were coordinately overexpressed and stabilized in both malignant cell lines. This pathway plays an important role in regulating cell growth and the development of malignancy. Numerous additional transcripts that encode proteins involved in growth regulation, damage repair and stress responses, posttranscriptional gene expression, and mitochondrial metabolism were also coordinately up-regulated and stabilized. Overall, our results suggest that abnormal mRNA stabilization in malignancy can lead to the overexpression of growth-regulatory genes and contribute to the malignant phenotype. D
GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer
Oncogene, 2009
Effective control of both cell survival and cell proliferation is critical to the prevention of oncogenesis and to successful cancer therapy. Using functional expression cloning, we have identified GAS5 (growth arrest-specific transcript 5) as critical to the control of mammalian apoptosis and cell population growth. GAS5 transcripts are subject to complex post-transcriptional processing and some, but not all, GAS5 transcripts sensitize mammalian cells to apoptosis inducers. We have found that, in some cell lines, GAS5 expression induces growth arrest and apoptosis independently of other stimuli. GAS5 transcript levels were significantly reduced in breast cancer samples relative to adjacent unaffected normal breast epithelial tissues. The GAS5 gene has no significant protein-coding potential but expression encodes small nucleolar RNAs (snoRNAs) in its introns. Taken together with the recent demonstration of tumor suppressor characteristics in the related snoRNA U50, our observations suggest that such snoRNAs form a novel family of genes controlling oncogenesis and sensitivity to therapy in cancer.
American Journal of Respiratory Cell and Molecular Biology, 1998
Interleukin-5 (IL-5) transcriptional activation and mRNA stability were investigated in a human T H 0 T-cell clone (SP-B21) and in nonclonal CD4 T H 2 cells, differentiated in vitro from peripheral blood T cells. Cells were stimulated with ␣-CD3 monoclonal antibody (mAb) with and without ␣-CD28 mAb. Comparison to other cytokine genes revealed aspects of mRNA regulation unique to IL-5. The half-life (t 1/2) of IL-5 mRNA, determined by addition of actinomycin D (ActinoD) or cyclosporin A (CSA) was longer (by у 2 h) than that of IL-2, IL-3, IL-4, interferon-␥ , or granulocyte/macrophage colony-stimulating factor. With the exception of IL-5, t 1/2 values were significantly shorter with CSA as the transcriptional inhibitor than with ActinoD. The t 1/2 value of IL-5 mRNA, but not the other cytokine transcripts, determined with either Acti-noD or CSA, was longer than predicted from the kinetics of steady-state mRNA decline. Co-stimulation of both cell types with ␣-CD28 mAb increased the stability of cytokine transcripts weakly, and IL-5 remained the most stable transcript. Thus, the degradation pathway that targets IL-5 is distinct from the other cytokine transcripts measured and involves proteins whose transcription is blocked by ActinoD and CSA. From examination of the levels of transcription initiation (nuclear run-on assay) and steady-state mRNA attained in cultures stimulated in the presence of the protein synthesis inhibitor, cycloheximide, only IL-5 transcription initiation had an absolute dependency on new protein synthesis.
Sequential expression of genes involved in human T lymphocyte growth and differentiation
Journal of Experimental Medicine, 1985
Nuclear transcription assays were performed with isolated nuclei from human peripheral blood T lymphocytes stimulated with phytohemagglutinin and phorbol myristate acetate to determine the kinetics of transcriptional activity of various genes occurring in T cell activation. Although silent in resting T cells, the genes encoding c-myc and the interleukin 2 (IL-2) receptor were induced early, preceding gamma interferon (IFN-gamma), IL-2, and transferrin receptor gene transcription. Transcriptional activity of these genes fell after their respective peaks, indicating that the expression of these genes is a transient event during T cell activation. With the exception of the transferrin receptor gene, the kinetics of induction of these genes were not altered by concentrations of cycloheximide that inhibited protein synthesis. These data indicate that the induction of genes encoding c-myc, IL-2, IL-2 receptor, and IFN-gamma occur independently of the sequential production of the proteins ...