Assembly and Maturation of the U3 snoRNP in the Nucleoplasm in a Large Dynamic Multiprotein Complex

Watkins, Nicholas J.; Lemm, Ira; Ingelfinger, Dierk; Schneider, Claudia; Hoßbach, Markus; Urlaub, Henning; Lührmann, Reinhard

doi:10.1016/j.molcel.2004.11.012

Cited by 162 publications

(241 citation statements)

References 48 publications

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“…We have previously shown an overexpression of Reptin in hepatocellular carcinoma (8) and that Reptin silencing reduced tumor cell growth and viability in vitro (8,9), a finding confirmed by others in a number of cell lines of different origins (10)(11)(12). Remarkably, Reptin silencing in vivo led to regression of hepatocellular carcinoma tumor xenografts, in association with the induction of tumor cell senescence (9).…”

Section: Introductionsupporting

confidence: 65%

“…Our data also lead us to conclude accordingly that antagonists of Reptin ATPase activity may be of benefit for the therapy of hepatocellular carcinoma. Besides hepatocellular carcinoma, an overexpression of Reptin has been shown in several types of tumors (2,11,12,27), and Reptin silencing also affects growth and viability of a variety of tumor cells (10)(11)(12). We thus propose that targeting Reptin ATPase activity may have broad applications in oncology.…”

Section: Discussionmentioning

confidence: 90%

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The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

Grigoletto

Neaud

Allain-Courtois

et al. 2013

Molecular Cancer Research

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Reptin is overexpressed in most human hepatocellular carcinomas. Reptin is involved in chromatin remodeling, transcription regulation, or supramolecular complexes assembly. Its silencing leads to growth arrest and apoptosis in cultured hepatocellular carcinoma cells and stops hepatocellular carcinoma progression in xenografts. Reptin has an ATPase activity linked to Walker A and B domains. It is unclear whether every Reptin function depends on its ATPase activity. Here, we expressed Walker B ATPase-dead mutants (D299N or E300G) in hepatocellular carcinoma cells in the presence of endogenous Reptin. Then, we silenced endogenous Reptin and substituted it with siRNA-resistant wild-type (WT) or Flag-Reptin mutants. There was a significant decrease in cell growth when expressing either mutant in the presence of endogenous Reptin, revealing a dominant negative effect of the ATPase dead mutants on hepatocellular carcinoma cell growth. Substitution of endogenous Reptin by WT Flag-Reptin rescued cell growth of HuH7. On the other hand, substitution by Flag-Reptin D299N or E300G led to cell growth arrest. Similar results were seen with Hep3B cells. Reptin silencing in HuH7 cells led to an increased apoptotic cell death, which was prevented by WT Flag-Reptin but not by the D299N mutant. These data show that Reptin functions relevant for cancer are dependent on its ATPase activity, and suggest that antagonists of Reptin

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 90%

The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

Grigoletto

Neaud

Allain-Courtois

et al. 2013

Molecular Cancer Research

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“…To reduce expression levels of the Pontin protein HeLa cells were transiently transfected with two siRNA duplexes (21-mers with 3′-dTdT overhangs) as described in Watkins et al (2004). Following the protocol of Elbashir et al (2002), siRNA oligonucleotides were annealed to produce siRNA duplexes.…”

Section: Sirnamentioning

confidence: 99%

Pontin is localized in nucleolar fibrillar centers

et al. 2008

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“…Small-interfering-RNA-mediated knockdown of La modestly decreased HeLa cell survival but was associated with more significant growth defects in the protozoan Trypanosoma brucei (10,32). A genetic analysis suggested that La is required during a late (larval) stage of development in Drosophila melanogaster (3).…”

mentioning

confidence: 99%

The Multifunctional RNA-Binding Protein La Is Required for Mouse Development and for the Establishment of EmbryonicStem Cells

Park

Kohn

Bruinsma

et al. 2006

Molecular and Cellular Biology

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The La protein is a target of autoantibodies in patients suffering from Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Ubiquitous in eukaryotes, La functions as a RNA-binding protein that promotes the maturation of tRNA precursors and other nascent transcripts synthesized by RNA polymerase III as well as other noncoding RNAs. La also associates with a class of mRNAs that encode ribosome subunits and precursors to snoRNAs involved in ribosome biogenesis. Thus, it was surprising that La is dispensable in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms from which it has been characterized most extensively. To determine whether La is essential in mammals and if so, at which developmental stage it is required, mice were created with a disrupted La gene, and the offspring from La ؉/؊ intercrosses were analyzed. La ؊/؊ offspring were detected at the expected frequency among blastocysts prior to implantation, whereas no nullizygotes were detected after implantation, indicating that La is required early in development. Blastocysts derived from La La antigen, also known as Sjögren's syndrome antigen B (SS-B), is a target of autoantibodies in patients suffering from systemic lupus erythematosus, neonatal lupus, and related disorders and exists in cells complexed with various RNAs (20). Homologs of La are present in all of the eukaryote genomes examined, and La proteins have been characterized in ciliates, yeasts, flies, frogs, and mammals (7,22,33). While La has been implicated in many RNA-related pathways, its most established role is protecting the UUU-OH 3Ј ends of precursor tRNAs and other small RNAs from digestion (21,23,29,33).Vertebrate La proteins can modulate the translation of mRNAs that contain internal ribosome entry sites, as well as mRNAs that contain 5Ј-terminal oligopyrimidine motifs that encode ribosome subunits and translation factors (8, 28; reviewed in reference 33). The association of human Mdm2 mRNA with La promotes MDM2 translation with consequent decrease in p53 protein level and leukemia progression (31). La is also found associated with mRNAs in Saccharomyces cerevisiae, including mRNAs that encode ribosome subunits (14). Deletion of La from yeasts leads to alterations in the maturation pathways of pre-tRNAs (2,5,6,16,17,26,35) and pre-snoRNAs involved in rRNA biogenesis (14, 21). Thus, it was surprising that La is nonessential in yeasts, except when tRNAs or RNA-associated factors acquire debilitating mutations (21, 29, 33) and upon a conditional induction of the unfolded protein response (14).The conserved N-terminal domain of La is comprised of a La motif and RNA recognition motif (RRM) that cooperate for high-affinity 3Ј UUU-OH binding (1, 9, 18). However, while these motifs constitute the La proteins of yeasts, metazoan La proteins also contain another, atypical RRM in their C termini (18).In the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms in which La has been characterized most extensively, La is dispens...

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Assembly and Maturation of the U3 snoRNP in the Nucleoplasm in a Large Dynamic Multiprotein Complex

Cited by 162 publications

References 48 publications

The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

The ATPase Activity of Reptin Is Required for Its Effects on Tumor Cell Growth and Viability in Hepatocellular Carcinoma

Pontin is localized in nucleolar fibrillar centers

The Multifunctional RNA-Binding Protein La Is Required for Mouse Development and for the Establishment of EmbryonicStem Cells

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