Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability

Cheadle, Chris; Fan, Jinshui; Cho‐Chung, Yoon S.; Werner, Thomas; Ray, Jill; Do, Lana; Gorospe, Myriam; Becker, Kevin G.

doi:10.1186/1471-2164-6-75

Cited by 172 publications

(146 citation statements)

References 25 publications

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“…During inflammatory processes, activation of neutrophils or T lymphocytes with IL-8 or phorbol 12-myristate 13-acetate, respectively, results in modulated up-regulation of many transcripts (28,29). Although a set of IL-8-or phorbol 12-myristate 13-acetate-induced genes is related to cell motility, no significant changes in PLD2 mRNA expression were observed in either cell type.…”

Section: Discussionmentioning

confidence: 76%

“…Although a set of IL-8-or phorbol 12-myristate 13-acetate-induced genes is related to cell motility, no significant changes in PLD2 mRNA expression were observed in either cell type. However, mTOR and S6K was consistently observed as up-regulated genes (29). This is probably due to the fact IL-8 actions on PLD2 transcripts are faster than the ones for mTOR/S6K.…”

Section: Discussionmentioning

confidence: 77%

“…In leukocytes, mRNA turnover via regulation of mRNA stability accounts for almost half of all changes in mRNA levels (29). Although the molecular aspects of PLD2 transcript up-regulation were not studied, IL-8-mediated PLD2 up-regulation observed in HL-60 cells may be under post-transcriptional control.…”

Section: Discussionmentioning

confidence: 99%

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Mammalian Target of Rapamycin (mTOR) and S6 Kinase Down-regulate Phospholipase D2 Basal Expression and Function

Tabatabaian¹,

Dougherty²,

Fulvio

et al. 2010

Journal of Biological Chemistry

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The mammalian target of rapamycin (mTOR) and S6 kinase (S6K) pathway is essential for cell differentiation, growth, and survival. Phospholipase D2 (PLD2) plays a key role in mTOR/ S6K mitogenic signaling. However, the impact of PLD on mTOR/S6K gene expression is not known. Here we show that interleukin-8 (IL-8) increases mRNA expression levels for PLD2, mTOR, and S6K, with PLD2 preceding mTOR/S6K in time. Silencing of PLD2 gene expression abrogated IL-8-induced mTOR/S6K mRNA expression, whereas silencing of mTOR or S6K gene expression resulted in large (>3-fold and >5-fold, respectively) increased levels of PLD2 RNA, which was paralleled by increases in protein expression and lipase activity. Treatment of cells with 0.5 nM rapamycin induced a similar trend. These results suggest that, under basal conditions, PLD2 expression and concomitant activity is negatively regulated by the mTOR/S6K signaling pathway. Down-regulation of PLD2 was confirmed in differentiated HL-60 leukocytes overexpressing an mTOR-wild type, but not an mTOR kinase-dead construct. At the cellular level, overexpression of mTOR-wild type resulted in lower basal cell migration, which was reversed by treatment with IL-8. We propose that IL-8 reverses an mTOR/ S6K-led down-regulation of PLD2 expression and enables PLD2 to fully function as a facilitator for cell migration. Phospholipase D (PLD)3 catalyzes the hydrolysis of the terminal diester bond of glycerophospholipids resulting in the formation of phosphatidic acid (PA) plus a related base in cell membranes. Two different genes encoding for mammalian phospholipase D exist: PLD1 and PLD2 (1-2). PLD-generated PA is a second messenger involved in mitogenesis, cell growth, and migration (3-6). Most significant effects of elevated PLD activity are mediated by targets of PA (6). Although several of these have been identified (7), we will concentrate on two of them, the mammalian target of rapamycin (mTOR) (8) and S6 kinase (S6K) (9). PA binds mTOR and activates it (8, 10). PA also binds and activates S6K independently of mTOR (9). Regardless, mTOR and/or S6K phosphorylates downstream targets resulting in the modulation of diverse cellular functions such as survival, cell migration and growth, and proliferation (6, 8, 10 -12).IL-8 is a potent chemoattractant that elicits cell migration in neutrophilic HL-60 cells (13), T lymphocytes, monocytes, and natural killer cells (14 -18). The PLD2 isozyme appears to be a functional target of IL-8-mediated activation of both CXCR1 and CXCR2, the two known receptors for 19). PLDderived PA mediates cell migration as well as mTOR/S6K activation (8 -10, 14). Indeed, the relevance of mTOR in cell migration and inflammation has been recently reported for T lymphocytes (20), macrophages (21), and neutrophils (22). Furthermore, leukocyte chemotaxis is inhibited by the macrolide immunosuppressant rapamycin, a specific inhibitor of the mTOR/S6K pathway (23).The impact of the mTOR/S6K signaling cascade and the role of this pathway on PLD function have not been investigate...

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 77%

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Mammalian Target of Rapamycin (mTOR) and S6 Kinase Down-regulate Phospholipase D2 Basal Expression and Function

Tabatabaian¹,

Dougherty²,

Fulvio

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…Because the half-lives of nascent transcripts are generally much shorter than those of mRNA (Griffiths-Jones, 2007; Mattick, 2009; Mercer et al, 2009; Wang and Chang, 2011), a short burst of transcription can result in elevated mRNA expression that lasts several hours, as has been shown in systems involving an acute inflammatory response (Cheadle et al, 2005; Hao and Baltimore, 2009). However, generic mRNA stability cannot account for this buffering, as many genes with arrhythmic but variable transcription do not exhibit rhythmic mRNA expression (Figure 6H).…”

Section: Discussionmentioning

confidence: 99%

Nascent-Seq reveals novel features of mouse circadian transcriptional regulation

Menet

Rodriguez

Abruzzi

et al. 2012

eLife

289

405

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A substantial fraction of the metazoan transcriptome undergoes circadian oscillations in many cells and tissues. Based on the transcription feedback loops important for circadian timekeeping, it is commonly assumed that this mRNA cycling reflects widespread transcriptional regulation. To address this issue, we directly measured the circadian dynamics of mouse liver transcription using Nascent-Seq (genome-wide sequencing of nascent RNA). Although many genes are rhythmically transcribed, many rhythmic mRNAs manifest poor transcriptional rhythms, indicating a prominent contribution of post-transcriptional regulation to circadian mRNA expression. This analysis of rhythmic transcription also showed that the rhythmic DNA binding profile of the transcription factors CLOCK and BMAL1 does not determine the transcriptional phase of most target genes. This likely reflects gene-specific collaborations of CLK:BMAL1 with other transcription factors. These insights from Nascent-Seq indicate that it should have broad applicability to many other gene expression regulatory issues.DOI: http://dx.doi.org/10.7554/eLife.00011.001

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“…In fact, recent data suggest that the processes of transcription and cytoplasmic mRNA decay may be much more tightly coordinated than previously suspected (Bregman et al 2011;Trcek et al 2011). Based on global analyses performed in response to various stimuli, z17%-50% of changes in mRNA levels are primarily a result of altered mRNA stability (Cheadle et al 2005;Schwanhäusser et al 2011). In addition, the cellular mRNA decay machinery rapidly and efficiently removes unwanted transcripts such as mRNAs with premature termination codons and damaged or malformed RNAs (Mühlemann and Jensen 2012).…”

Section: Introductionmentioning

confidence: 99%

A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability

Moon

Anderson

Kumagai

et al. 2012

RNA

185

251

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All arthropod-borne flaviviruses generate a short noncoding RNA (sfRNA) from the viral 39 untranslated region during infection due to stalling of the cellular 59-to-39 exonuclease XRN1. We show here that formation of sfRNA also inhibits XRN1 activity. Cells infected with Dengue or Kunjin viruses accumulate uncapped mRNAs, decay intermediates normally targeted by XRN1. XRN1 repression also resulted in the increased overall stability of cellular mRNAs in flavivirus-infected cells. Importantly, a mutant Kunjin virus that cannot form sfRNA but replicates to normal levels failed to affect host mRNA stability or XRN1 activity. Expression of sfRNA in the absence of viral infection demonstrated that sfRNA formation was directly responsible for the stabilization of cellular mRNAs. Finally, numerous cellular mRNAs were differentially expressed in an sfRNA-dependent fashion in a Kunjin virus infection. We conclude that flaviviruses incapacitate XRN1 during infection and dysregulate host mRNA stability as a result of sfRNA formation.

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Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability

Cited by 172 publications

References 25 publications

Mammalian Target of Rapamycin (mTOR) and S6 Kinase Down-regulate Phospholipase D2 Basal Expression and Function

Mammalian Target of Rapamycin (mTOR) and S6 Kinase Down-regulate Phospholipase D2 Basal Expression and Function

Nascent-Seq reveals novel features of mouse circadian transcriptional regulation

A noncoding RNA produced by arthropod-borne flaviviruses inhibits the cellular exoribonuclease XRN1 and alters host mRNA stability

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