Ataxin-2 promotes apoptosis of human neuroblastoma cells

Wiedemeyer, Ruprecht; Westermann, Frank; Wittke, Isabel; Nowock, Joachim; Schwab, Manfred

doi:10.1038/sj.onc.1206150

Cited by 54 publications

(37 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulation of ATXN2 sensitizes neuroblastoma cells of young children for apoptosis. Moreover, in neuroblastoma tumors, which contain an amplification of the MYCN gene, a significant lower ATXN2 concentration was observed in comparison with tumors without amplified MYCN (Wiedemeyer et al, 2003). In the first instance, we investigated whether increased intracellular levels of ATXN2 have an impact on Pbody structures.…”

Section: Discussionmentioning

confidence: 99%

“…In this case, we did not observe any effect on the cellular P-body structures (Figure 4). Together, these experiments demonstrate that an elevated cellular ATXN2 level, as observed in SCA2 patients and some neuroblastomas (Huynh et al, 1999;Koyano et al, 1999;Wiedemeyer et al, 2003), can interfere with the presence of P-body structures. …”

mentioning

confidence: 88%

“…Moreover, elevated ATXN2 levels sensitize certain neuroblastoma cells for apoptosis (Huynh et al, 1999;Koyano et al, 1999;Wiedemeyer et al, 2003). Therefore, we set out to directly investigate whether an elevated level of normal or diseasecausing expanded ATXN2 protein would have an impact on the cellular P-body structures.…”

Section: Elevated Atxn2 Levels Interfere With Cellular P-body Structuresmentioning

confidence: 99%

See 2 more Smart Citations

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

314

320

View full text Add to dashboard Cite

Tight control of translation is fundamental for eukaryotic cells, and deregulation of proteins implicated contributes to numerous human diseases. The neurodegenerative disorder spinocerebellar ataxia type 2 is caused by a trinucleotide expansion in the SCA2 gene encoding a lengthened polyglutamine stretch in the gene product ataxin-2, which seems to be implicated in cellular RNA-processing pathways and translational regulation. Here, we substantiate a function of ataxin-2 in such pathways by demonstrating that ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6, a component of P-bodies and stress granules, representing cellular structures of mRNA triage. We discovered that altered ataxin-2 levels interfere with the assembly of stress granules and cellular P-body structures. Moreover, ataxin-2 regulates the intracellular concentration of its interaction partner, the poly(A)-binding protein, another stress granule component and a key factor for translational control. Thus, our data imply that the cellular ataxin-2 concentration is important for the assembly of stress granules and P-bodies, which are main compartments for regulating and controlling mRNA degradation, stability, and translation. INTRODUCTIONAn essential step in the control of global gene expression in eukaryotes is the regulation of mRNA translation and degradation. Shortening of the poly(A) tail is the initial step to trigger mRNA for decay in two major mRNA degradation pathways in eukaryotic cells (Bernstein and Ross, 1989;Peltz et al., 1991;Decker and Parker, 1994;Beelman and Parker, 1995). In one pathway, the deadenylated mRNA is degraded by a cytoplasmic protein complex, the exosome, consisting of a number of exonucleases with 3Ј-5Ј activity (Butler, 2002). In the other pathway, shortening of the poly(A) tail leads to the removal of the cap structure of the mRNA by the decapping proteins DCP1 and DCP2 facilitating 5Ј-3Ј degradation of the mRNA through the exoribonuclease XRN1 (Beelman and Parker, 1995;Butler, 2002). These proteins colocalize in discrete cytoplasmic foci in mammalian cells, termed processing bodies or P-bodies (also known as DCP1-or GW182-bodies), indicating that mRNA decay is restricted to distinct cytoplasmic compartments in mammalian cells (van Dijk et al., 2002;Cougot et al., 2004). The human protein CCR4, which is involved in mRNA deadenylation, the decapping stimulating LSm proteins LSm1-7, the DEAD/Hbox RNA helicase DDX6 (also known as RCK/p54), GW182, and Ge-1 are components of P-bodies (Bouveret et al., 2000;Eystathioy et al., 2002;Ingelfinger et al., 2002; LykkeAndersen, 2002;Cougot et al., 2004;Yu et al., 2005). Moreover, the RNA-associated protein 55, hEDC3, Hedls as well as factors of the RISC complex localize to P-bodies in mammalian cells (Fenger-Gron et al., 2005;Liu et al., 2005;Sen and Blau, 2005;Yang et al., 2006). P-bodies represent dynamic structures that are in an equilibrium with polysomes and contain nontranslating mRNA . Remarkably, recent work demonstrated that mRNA molecules entering P-bodies can a...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

Section: Elevated Atxn2 Levels Interfere With Cellular P-body Structuresmentioning

confidence: 99%

See 1 more Smart Citation

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Nonhoff

Ralser

Welzel

et al. 2007

MBoC

314

320

View full text Add to dashboard Cite

show abstract

“…Its action has been related to RNA metabolism (Bravo et al 2005). Ataxin-2 reportedly has an important role in regulating the susceptibility of neuroblastoma cells to apoptotic stimuli (Wiedemeyer et al 2003). If ataxin-2 is overexpressed in yeast it causes premature cell death due to defects in actin filament formation (Satterfield et al 2002).…”

Section: Appearance Of Senescence Parameters Compared With Gene Exprementioning

confidence: 99%

Gene expression in opening and senescing petals of morning glory (Ipomoea nil) flowers

et al. 2007

View full text Add to dashboard Cite

We isolated several senescence-associated genes (SAGs) from the petals of morning glory (Ipomoea nil) flowers, with the aim of furthering our understanding of programmed cell death. Samples were taken from the closed bud stage to advanced visible senescence. Actinomycin D, an inhibitor of transcription, if given prior to 4 h after opening, suppressed the onset of visible senescence, which occurred at about 9 h after flower opening. The isolated genes all showed upregulation. Two cell-wall related genes were upregulated early, one encoding an extensin and one a caffeoyl-CoA-3-O-methyltransferase, involved in lignin production. A pectinacetylesterase was upregulated after flower opening and might be involved in cell-wall degradation. Some identified genes showed high homology with published SAGs possibly involved in remobilisation processes: an alcohol dehydrogenase and three cysteine proteases. One transcript encoded a leucine-rich repeat receptor protein kinase, putatively involved in signal transduction. Another transcript encoded a 14-3-3 protein, also a protein kinase. Two genes have apparently not been associated previously with senescence: the first encoded a putative SEC14, which is required for Golgi vesicle transport, the second was a putative ataxin-2, which has been related to RNA metabolism. Induction of the latter has been shown to result in cell death in yeast, due to defects in actin filament formation. The possible roles of these genes in programmed cell death are discussed.

show abstract

“…A study performed to identify genes associated with cell death in human neuroblastoma cells suggests that ATX2 is involved in regulating the sensitivity to apoptotic stimuli. 14 The interaction of the related thrombopoietin and erythropoietin receptors TPO-R and EPO-R with an ATX2 homolog, termed A2D, seemed to point to a functional role in cytokine signaling pathways. 15 Yeast-2-hybrid studies identified ATX2 as interaction partner of A2BP1 (ATX2 binding protein 1), a protein of unknown function, but with a putative RNA-recognition motif (RRM domain).…”

Section: Introductionmentioning

confidence: 99%

An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

Ralser

Albrecht

Nonhoff

et al. 2005

Journal of Molecular Biology

135

145

View full text Add to dashboard Cite

Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by a trinucleotide expansion in the SCA2 gene, encoding a polyglutamine stretch in the gene product ataxin-2 (ATX2), whose cellular function is unknown. However, ATX2 interacts with A2BP1, a protein containing an RNA-recognition motif, and the existence of an interaction motif for the C-terminal domain of the poly(A)-binding protein (PABC) as well as an Lsm (Like Sm) domain in ATX2 suggest that ATX2 like its yeast homolog Pbp1 might be involved in RNA metabolism. Here, we show that, similar to Pbp1, ATX2 suppresses the petite (pet K ) phenotype of Dmrs2 yeast strains lacking mitochondrial group II introns. This finding points to a close functional relationship between the two homologs. To gain insight into potential functions of ATX2, we also generated a comprehensive protein interaction network for Pbp1 from publicly available databases, which implicates Pbp1 in diverse RNA-processing pathways. The functional relationship of ATX2 and Pbp1 is further corroborated by the experimental confirmation of the predicted interaction of ATX2 with the cytoplasmic poly(A)-binding protein 1 (PABP) using yeast-2-hybrid analysis as well as co-immunoprecipitation experiments. Immunofluorescence studies revealed that ATX2 and PABP co-localize in mammalian cells, remarkably, even under conditions in which PABP accumulates in distinct cytoplasmic foci representing sites of mRNA triage.

show abstract

Ataxin-2 promotes apoptosis of human neuroblastoma cells

Cited by 54 publications

References 34 publications

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Ataxin-2 Interacts with the DEAD/H-Box RNA Helicase DDX6 and Interferes with P-Bodies and Stress Granules

Gene expression in opening and senescing petals of morning glory (Ipomoea nil) flowers

An Integrative Approach to Gain Insights into the Cellular Function of Human Ataxin-2

Contact Info

Product

Resources

About