Human La Protein: a Stabilizer of Histone mRNA

McLaren, Robert S.; Caruccio, Nicholas; Ross, Jeffrey

doi:10.1128/mcb.17.6.3028

Cited by 57 publications

(38 citation statements)

References 79 publications

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“…In addition to the well-described functions of the RNA-binding protein La in the processing of RNA polymerase III transcripts (for reviews, see Maraia, 2001;Wolin and Cedervall, 2002), the mammalian La interacts with both cellular (McLaren et al, 1997;Brenet et al, 2005) and viral mRNAs (Spangberg et al, 2001;Ehlers et al, 2004), and many reports suggest a role of La in regulation of cellular and viral translation. For instance, human La supports internal ribosome entry site (IRES)-and cap-dependent translation of viral mRNAs, such as hepatitis C virus, polio virus (Ali et al, 2000;Costa-Mattioli et al, 2004;Pudi et al, 2004), HIV TAR mRNA (Svitkin et al, 1994;Chang et al, 1995), suppresses translation of the hepatitis A virus (Cordes et al, 2008), and regulates IRES-and cap-dependent translation of cellular mRNAs (for example, BiP mRNA , X-linked inhibitor of apoptosis protein (Holcik and Korneluk, 2000), 5 0 TOP-mRNAs (Crosio et al, 2000) and Mdm2 mRNA (Trotta et al, 2003)).…”

Section: Introductionmentioning

confidence: 99%

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

et al. 2010

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The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.

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Section: Introductionmentioning

confidence: 99%

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

et al. 2010

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“…In cultured cells relocalization of the predominantly nuclear La protein into the cytoplasm during infection was frequently observed (24,25). Moreover, La protein was reported to stabilize not only cellular histone mRNA (26) but also RNA of hepatitis C virus (27).…”

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confidence: 99%

Functional Characterization of the Interaction between Human La and Hepatitis B Virus RNA

Ehlers

Horke

Reumann

et al. 2004

Journal of Biological Chemistry

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The La protein is a multifunctional RNA-binding protein and has also been suggested to be involved in the stabilization of hepatitis B virus (HBV) RNA. Here we demonstrate that antibodies against the human La protein specifically precipitate HBV RNA from HBV ribonucleoprotein-containing mammalian cell extracts, providing evidence for the association between human La and HBV RNA. Moreover, we report that the turnover of HBV RNA depends on structural features and less on the primary sequence of the La-binding site on the viral RNA. In addition we show that the interaction between human La and HBV RNA in vitro is modulated by accessory factor(s) in a phosphorylation-dependent manner. Taken together these data indicate that both structural features, the composition of La/HBV ribonucleoprotein particles as well as interacting cellular factors, are critical determinants in the regulation of the stability of the HBV RNA.RNA metabolism depends on the formation of ribonucleoprotein particles mediating diverse processes such as splicing, polyadenylation, nuclear export, and the regulation of mRNA stability (1, 2). The formation of RNPs 1 is a tightly controlled process, potentially regulated by several stimuli, including hormones and cytokines. Such stimuli can alter the RNA binding activity of proteins on the post-translational level by phosphorylation or dephosphorylation and thereby the processing and stability of RNAs (3-5). In addition, RNA processing depends on various cis-acting elements including splice sites, export elements, and endoribonucleolytic cleavage sites recognized by RNA-binding proteins. To understand fully the regulation of processing of a specific RNA, both trans-acting factors and cis-acting elements as well as their functions need to be known. The same applies for a detailed understanding of the metabolism of viral RNA. Such studies could lead to the identification of novel cellular targets valuable for the development of innovative antiviral strategies when focused on the post-transcriptional control of RNAs of viruses with global medical importance. This applies to hepatitis B virus (HBV) with more than 300 million chronically infected carriers worldwide who await more effective antiviral therapies.HBV is a noncytopathic, hepatotropic virus with a 3.2-kb circular DNA genome. After conversion into a covalently closed circular DNA, this genome serves in the nucleus as a template for transcription of all viral RNAs. Synthesis of these transcripts is driven by at least four promotors, leading to a large size heterogeneity with many different 5Ј-ends, whereas they all have very similar 3Ј-ends because of processing at the same polyadenylylation site (6). The so-called pregenomic RNA (slightly longer than genome length) is encapsidated into nucleocapsids where it is reverse-transcribed into viral DNA. This RNA serves also as messenger for synthesis of the viral P protein as well as for the core protein. The viral surface proteins as well as a regulatory protein with a role in hepatocarcinogenesis, des...

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“…The Walker A motif has instead been implicated in binding to the 5Ј-triphosphate ends of nascent tRNAs, with the affinity negatively modulated by phosphorylation of Ser 366 (4,7). Cytoplasmic functions for La have also been described, including facilitation of translation or replication of viral RNA and stabilization of histone mRNA (12,13).…”

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Contributions of the Individual Domains in Human La Protein to Its RNA 3′-End Binding Activity

Ohndorf

Steegborn

Knijff

et al. 2001

Journal of Biological Chemistry

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The autoantigen La regulates the maturation of RNA polymerase III transcripts by binding to their poly(U) termination signal. The modular protein harbors a Nterminal RNA recognition motif (RRM), RRM1, and in the C-terminal domain, a second, atypical RRM2, in addition to a phosphorylation site, and a putative nucleotide binding site. This study presents a detailed investigation into the RNA 3-end binding properties of La by using binding titration and competition assays with subsequent gel mobility shift analysis. Two truncation mutants containing one (La-RRM1) or both (La-RRM1-RRM2) RNA-binding domains were constructed, overexpressed, and purified. A K d value of 25 ؎ 10 nM for La binding to a nonameric RNA ligand with the oligouridylate recognition sequence was obtained, discriminating with a specificity ratio of ϳ100 for this probe over a RNA ligand with a 3-poly(A) stretch. The N-terminal La-RRM1 region was identified as the major contributor of these properties to La, manifested in a 5-fold lower K d of 5 ؎ 3 nM and a slightly increased specificity ratio of 120 for the RNA ligand. The atypical RRM2 in the C-terminal domain of La has an unprecedented negative effect on 3-end RNA recognition, as indicated by a higher K d value of 90 ؎ 10 nM for the La-RRM1-RRM2 mutant but comparable specificity. Thus the C-terminal regions beyond RRM2 positively modulate the RNA binding affinity of La. Negative regulation, however, occurs through Ser 366 phosphorylation decreasing the binding affinity by 2-fold. ATP had no influence on RNA complex formation. The functional implications of these findings for the mechanism of action of La are discussed.Human La protein (lupus antigen or La/SS-B) was originally identified as a major target of the autoimmune response in patients suffering from the autoimmune diseases Sjögren's syndrome and systemic lupus erythematosus (1). It is a conserved RNA-binding protein that recognizes specifically 3Ј-oligouridylate stretches (2). Associated with all RNA polymerase III transcripts where the 3Ј-UUU-OH sequence is added as the transcription termination signal, La is thought to play a central role in the metabolism of these RNAs by acting as a molecular chaperone that stabilizes and/or structures them for further processing (3). In HeLa cell extracts, the 5Ј-and 3Ј-end processing of tRNA precursors is influenced by La (4), and in vitro, La activity has been suggested in RNA polymerase termination, recycling, and initiation reactions (5-8). Furthermore, a Walker A nucleotide-binding motif in La was postulated to confer ATP-dependent RNA/DNA and RNA/RNA helicase activity (9, 10), but recently, the binding of La to double-stranded nucleic acids was shown to be independent of this site, and La does not appear to unwind double-stranded RNA (11). The Walker A motif has instead been implicated in binding to the 5Ј-triphosphate ends of nascent tRNAs, with the affinity negatively modulated by phosphorylation of Ser 366 (4, 7). Cytoplasmic functions for La have also been described, including facilitatio...

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Human La Protein: a Stabilizer of Histone mRNA

Cited by 57 publications

References 79 publications

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

Functional Characterization of the Interaction between Human La and Hepatitis B Virus RNA

Contributions of the Individual Domains in Human La Protein to Its RNA 3′-End Binding Activity

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