AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

Baou, Maria; Norton, John D.; Murphy, John J.

doi:10.1182/blood-2011-07-347237

Cited by 54 publications

(48 citation statements)

References 99 publications

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“…In addition to Hnrnpa0, which is haploinsufficient in del(5q) t-MN patients, several other genes encoding AUBPs were differentially expressed in t-MN patients with a del(5q) versus non-del(5q) t-MN patients (Online Supplementary Table S1). Since AUBPs can increase and/or decrease mRNA stability, depending on the cellular context, 13 their differential expression may indicate an intricate regulation of mRNA stability. Given the importance of AREs in disease, 12,26 we examined ARE-mRNAs that are differentially expressed in del(5q) versus other t-MN cases.…”

Section: Expression Of the Au-rich Transcriptome In T-mn Del(5q) Patimentioning

confidence: 99%

“…Moreover, the cytokinecytokine receptor interaction path was enriched in both of these gene lists (P=0.004 and P=0.003) ( Table 1). The control of mRNA stability is a key means of regulating cytokine production, 13 suggesting that Hnrnpa0 may be a positive or negative regulator of cytokine transcript stability, depending on the gene and cellular context. Alternatively, it remains possible that Hnrnpa0 KD may have had indirect effects on cytokine expression, independent of transcript stabilization.…”

Section: Gsea Analysis Reveals a Set Of Potential Hnrnpa0 Target Tranmentioning

confidence: 99%

“…13,15 HNRNPA0 expression is up-regulated by p38-dependent signaling in response to LPS, mycobacterial proteins, heat shock and IL-3 stimulation, and the protein is phosphorylated at Ser84 by MAPKAP-K2 downstream of p38 signaling, enabling it to bind to AU-rich mRNA targets. 10,16 Modulation of mRNA stability by HNRNPA0 has also been implicated in controlling cell cycle, especially with regard to DNA damage checkpoints.…”

Section: Introductionmentioning

confidence: 99%

“…HuR). 13 Moreover, it has been recognized that ARE-mediated decay and translational roles of AUBPs are influenced by miRNAs, the other well-known regulator of mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Expression Of the Au-rich Transcriptome In T-mn Del(5q) Patimentioning

confidence: 99%

Section: Gsea Analysis Reveals a Set Of Potential Hnrnpa0 Target Tranmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…HuR). 13 Moreover, it has been recognized that ARE-mediated decay and translational roles of AUBPs are influenced by miRNAs, the other well-known regulator of mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

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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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“…Independent of the micro-RNA pathway, AUBPs are known regulators of splicing, mRNA stability, translational efficiency, and RNA transport (3), and could provide an additional layer of developmental regulation that complements other pluripotency and self-renewal mechanisms. AUBPs are essential in many developmental systems, such as during hematopoiesis, neurogenesis, germ cell commitment, and placental morphogenesis (4)(5)(6). Their absence or misregulation can be lethal and often promotes disease progression (7)(8)(9).…”

mentioning

confidence: 99%

Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase

Tan

Elowitz

2014

Proc. Natl. Acad. Sci. U.S.A.

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AU-rich element mRNA-binding proteins (AUBPs) are key regulators of development, but how they are controlled and what functional roles they play depends on cellular context. Here, we show that Brf1 (zfp36l1), an AUBP from the Zfp36 protein family, operates downstream of FGF/Erk MAP kinase signaling to regulate pluripotency and cell fate decision making in mouse embryonic stem cells (mESCs). FGF/Erk MAP kinase signaling up-regulates Brf1, which disrupts the expression of core pluripotency-associated genes and attenuates mESC self-renewal without inducing differentiation. These regulatory effects are mediated by rapid and direct destabilization of Brf1 targets, such as Nanog mRNA. Enhancing Brf1 expression does not compromise mESC pluripotency but does preferentially regulate mesendoderm commitment during differentiation, accelerating the expression of primitive streak markers. Together, these studies demonstrate that FGF signals use targeted mRNA degradation by Brf1 to enable rapid posttranscriptional control of gene expression in mESCs.

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To Translate or Degrade: Cytoplasmic mRNA Decision Mechanisms

Beisang

Bohjanen

2014

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

Cited by 54 publications

References 99 publications

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

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

Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase

To Translate or Degrade: Cytoplasmic mRNA Decision Mechanisms

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