Inflammation Modulates the Interaction of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) I/Polypyrimidine Tract Binding Protein and hnRNP L with the 3′Untranslated Region of the Murine Inducible Nitric-Oxide Synthase mRNA

Söderberg, Malin; Raffalli-Mathieu, Françoise; Lang, Matti A.

doi:10.1124/mol.62.2.423

Cited by 42 publications

(32 citation statements)

References 39 publications

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“…Note that mammalian PTB1 was also shown to regulate mRNA stability. However, in all cases, PTB was shown to stabilize the target mRNA and lead to upregulation of gene expression (Kosinski et al 2003;Soderberg et al 2002;Tillmar and Welsh 2004). In trypanosomes, both PTB proteins can either stabilize or destabilize their mRNA targets.…”

Section: Ptb1 and Ptb2 Regulate Mrna Stabilitymentioning

confidence: 99%

“…PTB1 and PTB2 affect the stability of distinct sets of mRNAs In mammals, PTB was shown to govern the stability of mRNA by binding to the 39 UTR (Soderberg et al 2002;Kosinski et al 2003;Tillmar and Welsh 2004). To examine if PTB1 and PTB2 similarly regulate the stability of their substrates, the half-life of PTB1 and PTB2 target transcripts were examined.…”

Section: Validation Of the Microarray Datamentioning

confidence: 99%

“…In the cytoplasm, PTB has been shown to stabilize mammalian mRNAs by binding to the 39 UTR (Soderberg et al 2002;Kosinski et al 2003;Tillmar and Welsh 2004). In addition, PTB has been shown to regulate mRNA localization (Cote et al 1999) and internal ribosome entry site (IRES)-mediated translation during apoptosis (Bushell et al 2006).…”

Section: Introductionmentioning

confidence: 99%

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Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism

Stern¹,

Gupta²,

Salmon‐Divon³

et al. 2009

RNA

107

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Trypanosomatid genomes encode for numerous proteins containing an RNA recognition motif (RRM), but the function of most of these proteins in mRNA metabolism is currently unknown. Here, we report the function of two such proteins that we have named PTB1 and PTB2, which resemble the mammalian polypyrimidine tract binding proteins (PTB). RNAi silencing of these factors indicates that both are essential for life. PTB1 and PTB2 reside mostly in the nucleus, but are found in the cytoplasm, as well. Microarray analysis performed on PTB1 and PTB2 RNAi silenced cells indicates that each of these factors differentially affects the transcriptome, thus regulating a different subset of mRNAs. PTB1 and PTB2 substrates were categorized bioinformatically, based on the presence of PTB binding sites in their 59 and 39 flanking sequences. Both proteins were shown to regulate mRNA stability. Interestingly, PTB proteins are essential for trans-splicing of genes containing C-rich polypyrimidine tracts. PTB1, but not PTB2, also affects cis-splicing. The specificity of binding of PTB1 was established in vivo and in vitro using a model substrate. This study demonstrates for the first time that trans-splicing of only certain substrates requires specific factors such as PTB proteins for their splicing. The trypanosome PTB proteins, like their mammalian homologs, represent multivalent RNA binding proteins that regulate mRNAs from their synthesis to degradation.

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Section: Ptb1 and Ptb2 Regulate Mrna Stabilitymentioning

confidence: 99%

Section: Validation Of the Microarray Datamentioning

confidence: 99%

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Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism

Stern¹,

Gupta²,

Salmon‐Divon³

et al. 2009

RNA

107

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“…Eighteen proteins were identified (see Table S2 in the supplemental material). We focused on two proteins, hnRNP L and PTB (also known as hnRNP I), because PTB is known to regulate translation initiation from other IRES elements (9,56,65) and hnRNP L interacts with PTB (30,78). Alternative splicing gives rise to several isoforms of PTB (72).…”

Section: Identification Of Proteins That Form Complexes With Thementioning

confidence: 99%

The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

Majumder

Yaman

Gaccioli

et al. 2009

Molecular and Cellular Biology

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The response to amino acid starvation involves the global decrease of protein synthesis and an increase in the translation of some mRNAs that contain an internal ribosome entry site (IRES). It was previously shown that translation of the mRNA for the arginine/lysine amino acid transporter Cat-1 increases during amino acid starvation via a mechanism that utilizes an IRES in the 5 untranslated region of the Cat-1 mRNA. It is shown here that polypyrimidine tract binding protein (PTB) and an hnRNA binding protein, heterogeneous nuclear ribonucleoprotein L (hnRNP L), promote the efficient translation of Cat-1 mRNA during amino acid starvation. Association of both proteins with Cat-1 mRNA increased during starvation with kinetics that paralleled that of IRES activation, although the levels and subcellular distribution of the proteins were unchanged. The sequence CUUUCU within the Cat Cationic amino acid transporter 1 (Cat-1) is a high-affinity Na ϩ -independent transporter of L-arginine and L-lysine belonging to system yϩ (12, 62). Growth factors, hormones, and nutrients can modulate its expression level (20,53). Expression of the Cat-1 gene increases during stress in a manner that involves phosphorylation of translation initiation factor 2␣ (eIF2␣) (24). During such conditions, expression of the Cat-1 gene is regulated at the level of (i) mRNA synthesis via the transcription factor ATF4, which binds an amino acid response element in the first exon of the gene (54); (ii) mRNA stability via the binding of the nucleocytoplasmic protein HuR to an AU-rich element present within its 3Ј untranslated region (UTR) (94); and (iii) translation via a cap-independent mechanism of initiation via an internal ribosome entry site (IRES) (23).IRES-dependent translation involves the recruitment of ribosomes independently of the m 7 G cap at the 5Ј end of the mRNA followed by initiation downstream of the ribosome binding site (46). We showed that increased translation of the Cat-1 mRNA during amino acid starvation requires the translation of a 48-amino-acid open reading frame (ORF) in the 5Ј UTR of the mRNA, introducing the concept of a "dynamic IRES" (23,93). In the absence of upstream ORF (uORF) translation, the Cat-1 IRES remains in an inactive conformation. During starvation, translation of the uORF unwinds this secondary structure, leading to formation of a conformation that has IRES activity. Previous studies have also proposed that the active conformation is stabilized by proteins (IRES transactivating factors [ITAFs]) that are either synthesized or modified by processes that require eIF2␣ phosphorylation. We also showed that decreased translation elongation rates of the uORF in fed cells result in a prolonged half-life of this active remodeled structure, mimicking the role of ITAFs in amino acid-starved cells (21). Ribosome stalling within the uORF can occur physiologically during stresses that cause increased phosphorylation of elongation factor 2 and therefore decreased translation elongation rates (63). These two mechanisms o...

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“…PTB binds to oligopyrimidine tracts in introns and regulates negative or positive exon definition in differential splicing of various cellular mRNAs, like that for tropomyosin, a-actinin, the proto-oncogene c-src, a GABA receptor subunit, calcitonin/calcitonin gene-related peptide, and fibroblast growth factor-R2 (for reviews, see Valcárcel and Gebauer 1997;Wagner and Garcia-Blanco 2001;Spellman et al 2005). More recently PTB was described to be also involved in other aspects of RNA metabolism, like the modulation of polyadenylation efficiency (Castelo-Branco et al 2004) and the expression of nitric oxide synthase mRNA during inflammation (Soderberg et al 2002). Even a sex-specific role of PTB in the male germline of Drosophila flies was reported (Robida and Singh 2003).…”

Section: Introductionmentioning

confidence: 99%

Evidence for an RNA chaperone function of polypyrimidine tract-binding protein in picornavirus translation

Song

Tzima

Ochs

et al. 2005

RNA

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The cellular polypyrimidine tract-binding protein (PTB) is recruited by the genomic RNAs of picornaviruses to stimulate translation initiation at their internal ribosome entry site (IRES) elements. We investigated the contribution of the individual RNA recognition motif (RRM) domains of PTB to its interaction with the IRES of foot-and-mouth disease virus (FMDV). Using a native gel system, we found that PTB is a monomer, confirming recent reports that challenged the previous view that PTB is a dimer. Mapping the spatial orientation of PTB relative to the bound IRES RNA, we found that the two C-terminal RRM domains III and IV of PTB bind in an oriented way to the IRES. Domain III contacts the IRES stem-loop 2, while domain IV contacts the separate IRES 3¢ region. PTB domain I appears not to be involved directly in RNA binding, but domain II stabilizes the RNA binding conferred by domains III and IV. A PTB protein containing only these two C-terminal PTB domains is sufficient to enhance the entry of initiation factor eIF4G to the IRES and stimulate IRES activity, and the long-lived PTB-IRES interaction stabilized by domain II is not a prerequisite for this function. Thus, PTB most likely acts as an RNA chaperone to stabilize IRES structure and, in that way, augment IRES activity.

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Inflammation Modulates the Interaction of Heterogeneous Nuclear Ribonucleoprotein (hnRNP) I/Polypyrimidine Tract Binding Protein and hnRNP L with the 3′Untranslated Region of the Murine Inducible Nitric-Oxide Synthase mRNA

Cited by 42 publications

References 39 publications

Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism

Multiple roles for polypyrimidine tract binding (PTB) proteins in trypanosome RNA metabolism

The hnRNA-Binding Proteins hnRNP L and PTB Are Required for Efficient Translation of the Cat-1 Arginine/Lysine Transporter mRNA during Amino Acid Starvation

Evidence for an RNA chaperone function of polypyrimidine tract-binding protein in picornavirus translation

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