Perspectives on the ARE as it turns 25 years old

Beisang, Daniel; Bohjanen, Paul R.

doi:10.1002/wrna.1125

Cited by 48 publications

(44 citation statements)

References 111 publications

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“…AU-rich elements (AREs) are a specific subset of AU-rich sequences found in mammalian cis-acting tracts of 50 to 150 nucleotides (nt) that in humans reside within the 3= UTRs of 5 to 8% of mRNAs (6) and that consist of AUUUA pentamers, either overlapping or near other AU-rich sequences (7). ARE-containing mRNAs mostly encode proteins that are tightly regulated, e.g., transcription factors, cytokines, and cell-cycle-regulatory genes.…”

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confidence: 99%

LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

Mattijssen

Maraia

2016

Molecular and Cellular Biology

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bLARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3= untranslated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of ␤-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-␣), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-␣-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-␣-TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. L a-related protein 4 (LARP4), a member of the La family of proteins (1, 2), is a multimodular protein involved in mRNA metabolism. Unlike La protein, the most ancient member of the family, which binds most avidly to 3=-terminal oligo(U) tracts found on nascent transcripts and processing intermediates of small nuclear RNAs, LARP4 is predominantly cytoplasmic and binds preferentially to poly(A) RNA (2). LARP4 interacts with the MLLE domain of the cytoplasmic poly(A)-binding protein (PABPC1) via a well-characterized PAM2 motif near its N terminus (2). LARP4 independently interacts with the receptor for activated C kinase (RACK1), which associates with mRNAs and the 40S ribosome (2). Small interfering RNA (siRNA)-mediated knockdown of LARP4 decreased general protein synthesis (2). Modest overexpression of LARP4 conferred stability on some mRNAs more than others (2).LARP4 underwent a gene duplication event in an ancient vertebrate that gave rise to LARP4B, which has been independently maintained thereafter (3). The two genes are located on different human chromosomes and produce different proteins that each bind to PABP and RACK1 but likely exhibit different sequencespecific RNA binding (1, 2, 4). LARP4B promotes mRNA accumulation and translation by binding 3= untranslated region (UTR) AU-rich sequences of a set of mRNAs (4, 5). The data suggest that LARP4 and -4B modulate mRNA stability and translation but that they may target different sets of mRNAs.AU-rich elements (AREs) are a specific subset of AU-rich sequences found in mammalian cis-acting tracts of 50 to 150 nucleotides (nt) that in humans reside within the 3= UTRs of 5 to 8% of mRNAs (6) and that consist of AUUUA pentamers, either overlapping or near other AU-rich sequences (7). ARE-c...

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confidence: 99%

LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

Mattijssen

Maraia

2016

Molecular and Cellular Biology

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“…Bacterial cell wall products such as LPS bind to receptors on the macrophage and initiate a signal transduction cascade, resulting in TNF␣ transcription (1). For translation to occur, p38 MAPK must be activated to relieve translational silencing that is mediated, in part, by proteins interacting with AU-rich elements (AREs) 2 in the 3Ј-UTR of TNF␣ mRNA (2)(3)(4)(5)(6). One p38 MAPK substrate involved in regulating TNF␣ translation is Mnk1 (MAPK signal-integrating kinase 1) (7).…”

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Interleukin-10 Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Translation through a SHIP1-dependent Pathway

Chan

Ming-Lum

Golds

et al. 2012

Journal of Biological Chemistry

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Background: IL-10 inhibits TNF␣ expression in the anti-inflammatory response. Results: IL-10 activates SHIP1 phosphatase to inhibit TNF␣ translation through polysome disassembly and Mnk1 activation. Conclusion: SHIP1 is involved in the regulatory mechanism of IL-10 for controlling TNF␣ translation. Significance: This suggests a STAT3-independent pathway for IL-10 in controlling inflammation through SHIP1.

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“…However, like many other AUBPs, its regulatory ability may be more complex and regulated in a cell-type and activation-dependent manner. [38][39][40] The observed changes in transcript profiles upon Hnrnpa0 KD were numerous, yet small in magnitude for AU-rich genes, but also for some non-AU rich genes, suggesting that HNRPNA0 likely 'fine-tunes' gene expression, and that some of its effects on the pathogenesis of disease may be secondary to its post-transcriptional regulation. We attempted to explore the effects of Hnrpa0 loss in vivo; however, suppression of Hnrpa0 was not maintained past 12 weeks in the bone marrow of mice (data not shown).…”

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confidence: 99%

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

et al. 2014

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© F e r r a t a S t o r t i F o u n d a t i o nhave a profound impact upon hematopoiesis, and consequently contribute to the changes seen in t-MN patients.In this study, we now add HNRNPA0 to the growing list of AUBPs that are recognized for their vital roles in hematopoiesis and leukemogenesis. Herein, we show that HNRNPA0 is highly expressed in hematopoietic stem cells, and its expression exhibits dynamic changes during the course of differentiation. Deletion of a single allele of HNRNPA0 is associated with haploinsufficient transcript levels in CD34 + cells from t-MN patients with a del(5q). Modeling HNRNPA0 haploinsufficiency in mouse cells alters myeloid lineage fate, in part through changes in the expression of ARE-containing genes, suggesting that a decreased dose of HNRNPA0 in t-MN patients may contribute to leukemogenesis. Moreover, we determined that ARE mRNAs in t-MN patients with a del(5q) are enriched in transcripts that encode proteins associated with increased growth and proliferation. Methods Retroviral transduction and in vitro differentiation of PUER and primary mouse hematopoietic cellsA short interfering RNA hairpin (shRNA), designed to match bases 288 to 306 of the open reading frame of Hnrnpa0 with a 9 nucleotide loop in the center, or a scrambled, irrelevant sequence, 17 was cloned into pBanshee-GFP (an MSCV-based construct with P CMV -driven GFP). The PUER cell line or mouse bone marrow cells from BALB/cAnNTac mice (Taconic, Hudson, NY, USA) were transduced by spinoculation with viral supernatants from HEK-293T cells co-transfected with the shRNA-containing pBanshee and pCL-ECO packaging plasmids (Imgenex, San Diego, CA, USA) using Effectene (Qiagen, Germantown, MD, USA). Two days post infection, the cells were sorted on a FACSAria (BD Biosciences, San Jose, CA, USA) for GFP positivity. All animal studies were approved by the University of Chicago Institutional Animal Care and Use Committee and mice were housed in a fully-AALAC-accredited facility. GFP + sorted PUER cells, expressing the Hnrnpa0 or control shRNA, were expanded in IL-3 for four days and then treated with 1-5 nM 4-hydroxytamoxifen (4-OHT, >98% (TLC) Z-isomer, Sigma, St. Louis, MO, USA) to induce macrophage differentiation. For gene expression, flow cytometry and morphological analyses, cells were sampled at 24 h, 4 days, and 7days, respectively. GFP + bone marrow cells were plated in MethoCult GF M3434 (StemCell Technologies, Vancouver, BC, Canada). After 12 days of incubation, colonies of greater than 50 cells were scored for morphology by inverted light microscopy. Cells were then collected and stained with Mac-1 (CD11b) antibodies in combination with either F4/80 or Gr-1 (Ly-6G) antibodies, and analyzed on a FASCanto benchtop flow cytometric analyzer (BD Biosciences, San Jose, CA, USA). Patient samplesAll 38 t-MNs used for gene expression profiling analysis were obtained from patients treated with chemotherapy and/or radiation therapy at the University of Chicago who were diagnosed with t-MN between January 1984...

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Perspectives on the ARE as it turns 25 years old

Cited by 48 publications

References 111 publications

LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

Interleukin-10 Inhibits Lipopolysaccharide-induced Tumor Necrosis Factor-α Translation through a SHIP1-dependent Pathway

Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts

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