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PubMed2000

Heterogeneous nuclear ribonucleoprotein D0 contains transactivator and DNA-binding domains.

Heterogeneous nuclear ribonucleoprotein D0 (hnRNP D0) is an abundant, ubiquitous protein that binds RNA and DNA sequences specifically, and has been implicated in the transcriptional regulation of the human complement receptor 2 gene. We found that in vivo expression of hnRNP D0-GAL4 fusion proteins increased the transcriptional activity of a GAL4-driven reporter gene, providing direct proof that hnRNP D0 possesses a transactivator domain. We found, using truncated hnRNP D0 proteins fused to GAL4, that 29 amino acids in the N-terminal region are critical for transactivation. We established, using a series of recombinant truncated hnRNP D0 proteins, that the tandem RNA-binding domains alone were not able to bind double-stranded DNA. Nevertheless, 24 additional amino acids of the C-terminus imparted sequence-specific DNA binding. Experiments using peptide-specific antisera supported the importance of the 24-amino-acid region in DNA binding, and suggested the involvement of the 19-amino-acid alternative insert which is present in isoforms B and D. The N-terminus had an inhibitory effect on binding of hnRNP D0 to single-stranded, but not to double-stranded, DNA. Although both recombinant hnRNP D0B and D0D bound DNA, only the B isoform recognized DNA in vivo. We propose that the B isoform of hnRNP D0 functions in the nucleus as a DNA-binding transactivator and has distinct transactivator and DNA-binding domains.

Amino Acid Sequence↗

PubMed1995

The UUAG-specific RNA binding protein, heterogeneous nuclear ribonucleoprotein D0. Common modular structure and binding properties of the 2xRBD-Gly family.

Human cDNA clones encoding the UUAG-binding heterogeneous nuclear ribonucleoprotein (hnRNP) D0 protein have been isolated and expressed. The protein has two RNA-binding domains (RBDs) in the middle part of the protein and an RGG box, a region rich in glycine and arginine residues, in the C-terminal part ("2xRBD-Gly" structure). The hnRNP A1, A2/B1, and D0 proteins, all possess common features of the 2xRBD-Gly structure and binding specificity toward RNA. Together, they form a subfamily of RBD class RNA binding proteins (the 2xRBD-Gly family). One of the structural characteristics shared by these proteins is the presence of several isoforms presumably resulting from alternative splicing. Filter binding assays, using the recombinant hnRNP D0 proteins that have one of the two RBDs, indicated that one RBD specifically binds to the UUAG sequence. However, two isoforms with or without a 19-amino acid insertion at the N-terminal RBD showed different preference toward mutant RNA substrates. The 19-amino acid insertion is located in the N-terminal end of the first RBD. This result establishes the participation of the N terminus of RBD in determining the sequence specificity of binding. A similar insertion was also reported with the hnRNP A2/B1 proteins. Thus, it might be possible that this type of insertion with the 2xRBD-Gly type RNA binding proteins plays a role in "fine tuning" the specificity of RNA binding. RBD is supposed to bind with RNA in general and sequence-specific manners. These two discernible binding modes are proposed to be performed by different regions of the RBD. A structural model of these two binding sites is presented.

Alternative Splicing↗

PubMed1999

Structure and interactions with RNA of the N-terminal UUAG-specific RNA-binding domain of hnRNP D0.

Heterogeneous nuclear ribonucleoprotein (hnRNP) D0 has two ribonucleoprotein (RNP)-type RNA-binding domains (RBDs), each of which can bind solely to the UUAG sequence specifically. The structure of the N-terminal RBD (RBD1) determined by NMR is presented here. It folds into a compact alphabeta structure comprising a four-stranded antiparallel beta-sheet packed against two alpha-helices, which is characteristic of the RNP-type RBDs. Special structural features of RBD1 include N-capping boxes for both alpha-helices, a beta-bulge in the second beta-strand, and an additional short antiparallel beta-sheet coupled with a beta-turn-like structure in a loop. Two hydrogen bonds which restrict the positions of loops were identified. Backbone resonance assignments for RBD1 complexed with r(UUAGGG) revealed that the overall folding is maintained in the complex. The candidate residues involved in the interactions with RNA were identified by chemical shift perturbation analysis. They are located in the central and peripheral regions of the RNA-binding surface composed of the four-stranded beta-sheet, loops, and the C-terminal region. It is suggested that non-specific interactions with RNA are performed by the residues in the central region of the RNA-binding surface, while specific interactions are performed by those in the peripheral regions. It was also found that RBD1 has the ability to inhibit the formation of the quadruplex structure.

Amino Acid Sequence↗

PubMed2000

Heterogeneous nuclear ribonucleoproteins as regulators of gene expression through interactions with the human thymidine kinase promoter.

In search for nuclear proteins that interact with the human thymidine kinase (htk) promoter, we discovered that p37AUF, a hnRNP C-like protein, and hnRNP A1, both members of the heterogeneous ribonucleoprotein family, can bind with high affinity to an ATTT sequence motif contained within the cell cycle regulatory unit (CCRU). We report here that over-expression of p37AUF stimulates gene expression mediated by the htk promoter in a promoter-sequence specific manner, whereas hnRNP A1 suppresses it. Both recombinant p37AUF and hnRNP A1 can bind the htk CCRU, suggesting that their binding to the DNA target does not require additional cellular components. We further discovered that hnRNP K is a potent suppressor of htk mediated gene activity. However, its mechanism of action is mediated through protein-protein interaction, since hnRNP K itself cannot bind the htk CCRU but can competitively inhibit the binding of other hnRNPs. The binding site for the hnRNPs on the htk CCRU is not required for S-phase induction of the htk promoter. However, in stable but not transient transfectants, the mutation of the hnRNP binding site results in 5- to 10-fold reduction of htk mediated gene activity in synchronized and exponentially growing cells. Collectively, these findings support emerging evidence that hnRNPs, in addition to their traditional role in RNA biogenesis, could be regulators of gene expression through direct DNA binding or interaction with other proteins.

Amino Acid Sequence↗

PubMed2004

Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms.

The SH2D1A gene, which is altered or deleted in patients with X-linked lymphoproliferative disease, encodes the small protein SAP (for SLAM-associated protein) that is expressed in T and NK cells. A 22-bp fragment in close proximity to an initiator-like site was defined as the basal promoter of mouse SH2D1A, and a highly homologous 33-bp segment was defined as the human basal promoter. When an Ets consensus site was mutated, no reporter activity was detectable. Gel mobility supershift assays revealed that the two transcription factors Ets-1 and Ets-2 bind to the human and mouse sequences. The involvement of Ets-1 and Ets-2 in expression of SH2D1A was functionally confirmed by overexpression studies of their dominant-negative forms. We also found that SH2D1A mRNA decays very rapidly in mouse T cells, and its 3' untranslated region (UTR) has RNA-destabilizing activity in transfection studies with reporter/3' UTR constructs. As judged by RNA-gel mobility shift assays, this rapid degradation of SH2D1A mRNA was due to a balance in binding of the factors AUF1 and HuR to its 3' UTR. Although the SH2D1A mRNA level decreased upon triggering of the T cell receptor (TCR), the RNA degradation rate itself was not altered by TCR engagement.

3' Untranslated Regions↗

PubMed2006

AUF1-like protein binds specifically to DAS cis-acting element that regulates mouse alpha-fetoprotein gene expression.

Alpha-fetoprotein (AFP) is one of the major serum proteins in the early life of mammals. We have previously identified a novel cis-acting element designated as DAS at the 5'-flanking region of the AFP gene and demonstrated that the DAS sequence can be specifically recognized by nuclear protein DAP-II in AFP-producing hepatoma cells and retinoic acid (RA)-induced AFP-producing F9 cells. In this study, we used DNA affinity chromatography to purify the DAP-II proteins from the nuclear extracts (NE) of RA-treated F9 cells. The purified DAP-II complex mainly contained five proteins, with molecular weights of 45, 42, 32, 30, and 20 kDa, respectively. The identification of these proteins was determined by MALDI-TOF mass spectrometric analysis and a database search. These proteins were found to belong to the AUF1 RNA-binding protein family. Protein (30 kDa), one of five proteins in an isolated DAP-II complex, was matched with amino acid sequence highly similar to muAUF1-3. The expression of this protein is inducible by RA, and the pattern of the protein expression is the same as DAP-II proteins in F9 cells after treatment with RA during differentiation. Our results suggest that the 30-kDa protein is a novel isoform of AUF1 family and is the main component of the DAP-II complex that binds to the DAS sequence.

Amino Acid Sequence↗

PubMed2006

AUF-1 mediates inhibition by nitric oxide of lipopolysaccharide-induced matrix metalloproteinase-9 expression in cultured astrocytes.

Neuroinflammatory diseases are associated with increased production of matrix metalloproteinase-9 (MMP-9) and excessive generation of nitric oxide (NO). NO has been reported to have variable effects on MMP-9 gene expression and activation in various cell types. In the present study, we investigated the effect of NOon MMP-9 expression in primary cortical astrocytes. Zymography and real-time PCR showed that lipopolysaccharide (LPS) dramatically increased latent MMP-9 gelatinolytic activity and MMP-9 mRNA expression. By using the NO donor DETA NONOate, we observed a dose-dependent inhibition of MMP-9 induction by LPS. Active forms of MMP-9 were not found by zymography after NO treatment. The MEK1/2 inhibitor U0126 completely inhibited LPS-induced MMP-9, which was partially inhibited by the p38 MAPK inhibitor SB203580. NO had no effect on LPS-stimulated ERK1/2 and p38 MAPK activation, suggesting that the inhibitory action of NO occurs downstream of MAPK cascades. Real-time PCR analysis showed that NO accelerated the degradation of MMP-9 mRNA after LPS induction. Western blotting and pull-down assay demonstrated that NO increased AUF-1 expression as well as its specific binding to the MMP-9 gene 3'-untranslated region. Knockdown of AUF-1 with siRNA partially reversed the inhibitory action of NO on LPS-stimulated MMP-9 induction. We conclude that NO does not activate MMP-9 in astrocyte cultures but reduces LPS-induced MMP-9 expression via accelerating MMP-9 mRNA degradation, which is partially mediated by AUF-1. Our results suggest that elevated NO concentrations may suppress MMP-9 and restrict the inflammatory response in neurodegenerative diseases.

Animals↗

PubMed2000

A nuclear matrix-associated factor, SAF-B, interacts with specific isoforms of AUF1/hnRNP D.

One class of heterogeneous nuclear ribonucleoproteins (hnRNPs), AUF1/hnRNP D, consists of four isoform proteins (p45, p42, p40, and p37) which are generated by alternative splicing. The present study was therefore undertaken to clarify any isoform-specific differences in terms of their functions and nucleocytoplasmic localization. All isoforms primarily localized in the nucleus. However, heterokaryon analysis and a study using RNA polymerase II inhibitor revealed that p40/p37 exhibited a continuous shuttling between the nucleus and cytoplasm. Constant nuclear retention activity was mapped to the p45/p42-specific sequence at the C-terminal region, which is retained by alternative splicing. Using this domain as a probe, we performed a yeast two-hybrid screening and we found that scaffold attachment factor B (SAF-B), a nuclear matrix-associated protein, exhibits protein-protein interaction to this region. Colocalization of p45/p42 and SAF-B was observed as a speckle in the nucleus. Interestingly, p45/p42 isoforms appeared to act as a negative regulator in gene expression by forming a complex with SAF-B. Thus, the present study revealed that the isoform-specific functions of AUF1/hnRNP D are defined by intracellular shuttling capacity.

3T3 Cells↗

PubMed1999

Characterization of the binding of the RNA-binding protein AUF1 to the human AT(1) receptor mRNA.

An important mechanism of regulation of the expression of the AT(1) receptors is the modulation of the mRNA stability. AUF1, a human RNA-binding protein, may play an important role. Since AUF1 seems to bind to AU-rich regions of the 3'-untranslated region of the mRNAs, we verified the nucleotide sequence of human AT(1) receptor 3'-untranslated region and we found possible binding sites. In addition we evaluated the expression of the AUF1 protein in human vascular smooth muscle cells: the administration of both isoproterenol and angiotensin II induced a significant increase of total anti-AUF1 immunoreactive isoforms. At the same time angiotensin II induced a significant decrease in the AT(1) receptor mRNA abundance. Moreover, we found that recombinant human AUF1 protein binds to human AT(1) receptor riboprobes. The protein was able to bind to the distal portion of the 3'-untranslated region, and also to the coding region. Since the clinically relevant AT(1) receptor polymorphism is located in the 3'-untranslated region, we created two DNAs, corresponding to the A and C polymorphism, without any differences. Our data demonstrate the presence of AUF1 in human vascular smooth muscle cells and its modulation by activation of the beta-adrenergic and the AT(1) pathways, a and specific binding of AUF1 to the human AT(1) receptor mRNA, suggesting a role of this protein in the modulation of the AT(1) receptor expression.

3' Untranslated Regions↗

PubMed1996

Localization and physical mapping of genes encoding the A+U-rich element RNA-binding protein AUF1 to human chromosomes 4 and X.

Messenger RNAs encoding many oncoproteins and cytokines are relatively unstable. Their instability, which ensures appropriate levels and timing of expression, is controlled in part by proteins that bind to A+U-rich instability elements (AREs) present in the 3'-untranslated regions of the mRNAs. cDNAs encoding the AUF1 family of ARE-binding proteins were cloned from human and murine cDNA libraries. In the present study monochromosomal somatic cell hybrids were used to localize two AUF1 loci to human chromosomes 4 and X. In situ hybridization analyses using P1 clones as probes identified the 4q21.1-q21.2 and Xq12 regions as the locations of the AUF1 genes.

Animals↗

PubMed1998

Structure and genomic organization of the human AUF1 gene: alternative pre-mRNA splicing generates four protein isoforms.

The steady-state levels of many mRNAs are determined in part by their turnover rates. Turnover rates, in turn, are usually controlled by proteins that bind cis-acting sequence elements in mRNAs. One class of cis-acting instability determinants is composed of A + U-rich elements present in the 3'-UTRs of many labile mRNAs. Many A + U-rich elements are bound by the AUF1 family of RNA-binding proteins, which may target these mRNAs for rapid decay. cDNA cloning and immunoblot analyses suggest that the AUF1 family consists of at least four isoforms. Previous genomic cloning combined with FISH and Southern analyses of a panel of monochromosomal mouse/human or hamster/human somatic cell hybrids localized two AUF1 loci to human 4q21.1-q21.2 and Xq12 (B. Wagner et al., 1996, Genomics 34: 219-222). In the present study AUF1 gene organization was examined. The results suggest that the four known AUF1 isoforms are generated by alternative pre-mRNA splicing of a transcript encoded by the chromosome 4 locus. Functionally, this creates isoforms with different RNA-binding affinities and specificities. Thus, alternative pre-mRNA splicing may serve to create functional versatility within the AUF1 family of proteins.

Alternative Splicing↗

PubMed1999

Identification and characterization of proteins binding A + U-rich elements.

A + U-Rich elements (AREs) have been extensively investigated as cis-acting determinants of rapid mRNA turnover. Recently, a number of RNA-binding proteins interacting with AREs have been described. This article presents strategies and techniques used by our laboratory to identify and characterize a family of ARE-binding proteins collectively termed AUF1. However, these techniques may be applied to the study of any protein displaying sequence-specific RNA binding activity. The techniques described here include the purification of native AUF1 from cultured cells as well as the preparation of recombinant AUF1 proteins using a bacterial expression system. Analyses of RNA-protein interactions are also described, including the use of gel mobility shift assays with synthetic RNA probes to monitor specific RNA binding activity in cell extracts or with recombinant proteins. Variations of this technique are also described to evaluate the RNA binding affinity of recombinant proteins and the use of specific RNA competitors to assess RNA determinants of protein binding specificity. Other techniques presented include the identification of specific proteins in RNA:protein complexes using antibody supershifts and the estimation of molecular weights of RNA-binding proteins by UV crosslinking. Results of individual experiments are presented as examples of some techniques. Throughout the article, suggestions are included to avoid commonly encountered problems and to assist in the optimization of these techniques for the study of other RNA-binding proteins.

Adenine↗

PubMed1994

Characterization of cDNAs encoding the murine A+U-rich RNA-binding protein AUF1.

A+U-rich elements (ARE) serve to control the degradation of some proto-oncogene and lymphokine mRNAs. The protein, AUF1, which consists of two polypeptides of 37 and 40 kDa (p37 and p40, respectively) when purified from cytosol, has been implicated in ARE-directed mRNA turnover due to its binding to ARE. Molecular cloning of a cDNA (p37AUF1) corresponding to human p37 predicted a polypeptide containing two non-identical RNA recognition motifs (RRM) and a C-terminal Gln-rich domain [Zhang et al. Mol. Cell. Biol. 13 (1993) 7652-7665]. Two cDNAs, designated muAUF1-3 and muAUF1-7, were isolated from a murine fetal cDNA library, using as a probe, a fragment of the p37AUF1 cDNA encoding RRM1 and approximately half of RRM2. The muAUF1-3 open reading frame (ORF) was very homologous to human p37AUF1 with the greatest homology between the corresponding RRMs and the C-terminal Gln-rich motif. Clone muAUF1-7 was highly homologous to muAUF1-3, but was truncated within the region encoding the RNP-1 box in RRM2. Clone muAUF1-3 encoded 19 amino acids in RRM1 not encoded by either muAUF1-7 or human p37AUF1. Such alterations in sequence could modify the RNA-binding properties of these proteins and have concomitant effects on ARE-directed posttranscriptional processes.

Adenine↗

PubMed2006

LPL-mediated lipolysis of VLDL induces an upregulation of AU-rich mRNAs and an activation of HuR in endothelial cells.

Lipoprotein lipase (LPL), the major enzyme for hydrolysis of circulating triglyceride-rich lipoproteins, is bound to the luminal surface of capillary endothelial cells. Products of LPL-mediated lipolysis, such as free fatty acids (FFA) and lipoprotein-remnants, can affect endothelial function and gene expression, and hence vascular homeostasis. In this study we tried to identify lipolysis-induced mRNAs in porcine aortic endothelial cells (ECAP) using a cDNA subtraction method. cDNA obtained from ECAP incubated with LPL and VLDL was subtracted from cDNA from cells cultured under control conditions. Analysis of the identified sequences revealed an upregulation of several mRNAs with adenine and uracil-rich elements (ARE) in their 3'-untranslated regions, such as IL-8, ESM-1 and VCAM-1. HuR, a ubiquitously expressed RNA-binding protein, is known to stabilize ARE-harboring mRNAs. Therefore, we investigated whether HuR is involved in this process and found that lipolysis induced an increased polysomal localization of HuR, which is typical for its activation pathway. In addition, the mRNAs for GM-CSF and TNF-alpha - established ARE-containing targets for HuR-mediated regulation - were upregulated by LPL-mediated lipolysis in ECAP. Differential expression of AU-rich mRNAs in response to LPL-mediated lipolysis might have an impact on physiological processes regulating lipid metabolism or pathophysiological processes promoting endothelial dysfunction and atherogenesis.

Animals↗

PubMed2006

Differential regulation of ARE-mediated TNFalpha and IL-1beta mRNA stability by lipopolysaccharide in RAW264.7 cells.

Messenger RNA degradation is a mechanism by which eukaryotic cells regulate gene expression and influence cell growth and differentiation. Many protooncogene, cytokine, and growth factor RNAs contain AU-rich element (AREs) in the 3'untranslated regions which enable them to be targeted for rapid degradation. To investigate the mechanism of ARE-mediated RNA stability, we demonstrate the expression and regulation of TNFalpha and IL-1beta mRNAs in LPS-stimulated macrophages. TNFalpha mRNA was rapidly induced by LPS and showed short half-life at 2-h induction, whereas IL-1beta mRNA was induced slowly and had longer half-life. Electrophoretic mobility shift assays showed that the LPS-induced destabilization factor tristetraprolin (TTP) could bind to TNFalpha ARE with higher affinity than to IL-1beta ARE. HuR was identified to interact with TNFalpha ARE to exert RNA stabilization activity. The expression and phosphorylation of TTP could be activated by p38 MAPK pathway during LPS stimulation. Moreover, ectopic expression with TTP and kinases in p38 pathway followed by biochemical assays showed that the activation of p38 pathway resulted in the phosphorylation of TTP and a decrease in its RNA-binding activity. The ARE-containing reporter assay presented that the p38 signal could reverse the inhibitory activity of TTP on IL-1beta ARE but not on TNFalpha ARE. The present results indicate that the heterogeneity of AREs from TNFalpha and IL-1beta could reflect distinct ARE-binding proteins to modulate their RNA expression.

Animals↗

PubMed2006

Control of protein expression through mRNA stability in calcium signalling.

Specific sequences (cis-acting elements) in the 3'-untranslated region (UTR) of RNA, together with stabilizing and destabilizing proteins (trans-acting factors), determine the mRNA stability, and consequently, the level of expression of several proteins. Such interactions were discovered initially for short-lived mRNAs encoding cytokines and early genes like c-jun and c-myc. However, they may also determine the fate of more stable mRNAs in a tissue and disease-dependent manner. The interactions between the cis-acting elements and the trans-acting factors may also be modulated by Ca(2+) either directly or via a control of the phosphorylation status of the trans-acting factors. We focus initially on the basic concepts in mRNA stability with the trans-acting factors AUF1 (destabilizing) and HuR (stabilizing). Sarco/endoplasmic reticulum Ca(2+) pumps, SERCA2a (cardiac and slow twitch muscles) and SERCA2b (most cells including smooth muscle cells), are pivotal in Ca(2+) mobilization during signal transduction. SERCA2a and SERCA2b proteins are encoded by relatively stable mRNAs that contain cis-acting stability determinants in their 3'-regions. We present several pathways where 3'-UTR mediated mRNA decay is key to Ca(2+) signalling: SERCA2a and beta-adrenergic receptors in heart failure, renin-angiotensin system, and parathyroid hormones. Other examples discussed include cytokines vascular endothelial growth factor, endothelin and endothelial nitric oxide synthase. Roles of Ca(2+) and Ca(2+)-binding proteins in mRNA stability are also discussed. We anticipate that these novel modes of control of protein expression will form an emerging area of research that may explore the central role of Ca(2+) in cell function during development and in disease.

3' Untranslated Regions↗

PubMed2005

The c-Yes 3'-UTR contains adenine/uridine-rich elements that bind AUF1 and HuR involved in mRNA decay in breast cancer cells.

c-Yes is a member of the c-Src family of tyrosine kinases and has been implicated in intracellular signaling, cell morphology, and adhesion. Changes in its expression have also been associated with the aggressiveness of human breast and colon cancer cells. In MDA-MB-231 human breast cancer cells, overexpression of the small heat shock protein 27 (hsp27) results in a downregulation of c-Yes levels, concomitant with increased in vitro invasiveness and in vivo metastatic behavior. Very little is known, however, about the mechanisms regulating c-Yes expression. Here, we demonstrate that hsp27-induced c-Yes downregulation is not due to a reduction in transcriptional activity. However, the 3'-untranslated region (3'-UTR) of the c-Yes gene may be involved in its own regulation, since this region affects heterologous reporter gene activity in transactivation assays. This down-regulatory effect maps to three adenine/uridine-rich elements (AREs) that bind to cellular HuR and AUF1 (hnRNP D), two ARE-binding proteins (ARE-BPs) implicated in accelerated mRNA degradation. Our results suggest that the c-Yes 3'-UTR contains at least three newly identified AREs which are bound specifically by ARE-BPs, and provide a structural basis for post-transcriptional regulation of c-Yes expression.

3' Untranslated Regions↗

PubMed2004

A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery.

Inherently unstable mRNAs contain AU-rich elements (AREs) in their 3' untranslated regions that act as mRNA stability determinants by interacting with ARE binding proteins (ARE-BPs). The mechanisms underlying the function of ARE and ARE-BP interactions in promoting mRNA decay are not fully understood. Here, we demonstrate that KSRP, a KH domain-containing ARE-BP, is an essential factor for ARE-directed mRNA decay. Some of the KH motifs (KHs) of KSRP directly mediate RNA binding, mRNA decay, and interactions with the exosome and poly(A) ribonuclease (PARN). The ability of KHs to promote mRNA decay correlates with their ability to bind the ARE and associate with RNA-degrading enzymes. Thus, KHs promote rapid mRNA decay by recruiting degradation machinery to ARE-containing mRNAs.

3' Untranslated Regions↗