Heterogeneous Nuclear Ribonucleoprotein F/H Proteins Modulate the Alternative Splicing of the Apoptotic Mediator Bcl-x

Garneau, Daniel; Revil, Timothée; Fisette, Jean-François; Chabot, Benoît

doi:10.1074/jbc.m501070200

Cited by 195 publications

(243 citation statements)

References 39 publications

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“…5a), we performed in vitro splicing assays in HeLa nuclear extracts in the presence of increasing amounts of the individual qRRMs. It was shown previously that the activity of hnRNP F on Bcl-x splicing required the presence of the G-tracts located downstream of the Bcl-x S 5' splice site 18 . As shown in Figures 5b, 5d, and 5e, the addition of hnRNP F, qRRM1, or qRRM3 but not qRRM2 modified the Bcl-x L /Bcl-x S ratio towards the Bcl-x S isoform.…”

Section: Single Qrrms Of Hnrnp F Regulate the Splicing Of Bcl-xmentioning

confidence: 93%

“…Some of the trans-acting factors that bind to these G-tracts belong to the heterogeneous nuclear ribonucleoprotein (hnRNP) F/H family of proteins that consists of five members (hnRNP F, hnRNP H, hnRNP H', hnRNP 2H9, and GRich Sequence Factor (GRSF) 1) 9,10 . GRSF-1 is mainly involved in translation regulation 11,12 and Internal Ribosome Entry Site (IRES) mediated translation 13 , while hnRNP H, H' and F are mostly involved in the regulation of alternative splicing [14][15][16][17][18][19][20][21][22][23] and polyadenylation [24][25][26] . The posttranscriptional regulation by hnRNP F/H proteins is a crucial event since mutations in G-tracts often result in aberrant splicing patterns and can be associated with various diseases [27][28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

“…HnRNP F and H regulate the alternative splicing of the apoptotic regulator B-cell lymphoma/leukemia-2 (Bcl-2) related protein Bcl-x 18 . Bcl-x naturally exists in two forms, Bcl-x L (233 amino acids) and Bcl-x S (170 amino acids), which result from alternative 5' splice site utilization, producing a truncated exon 2 for Bcl-x S 36 .…”

Section: Introductionmentioning

confidence: 99%

“…The ratio of Bcl-x S and Bcl-x L is regulated by hnRNP F and H. These proteins recognize three G-tracts downstream of the Bcl-x S 5' splice site to encourage the production of the Bcl-x S isoform 18 .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs

Dominguez

Fisette

Chabot

et al. 2010

Nat Struct Mol Biol

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The heterogeneous nuclear ribonucleoprotein (hnRNP) F is involved in the regulation of mRNA metabolism by specifically recognizing G-tract RNA sequences. We have determined the solution structures of the three quasi RNA recognition motifs (qRRMs) of hnRNP F in complex with G-tract RNA. These structures show that qRRMs bind RNA in a very unusual manner, the G-tract being "encaged", making the qRRM a novel RNA binding domain. We defined a consensus signature sequence for qRRMs and identified other human qRRM-containing proteins, which also specifically recognize G-tract RNAs. Our structures explain how qRRMs can sequester G-tracts maintaining them in a single-stranded conformation. We also show that isolated qRRMs of hnRNP F are sufficient to regulate the alternative splicing of the Bcl-x premRNA strongly suggesting that hnRNP F would act by remodeling RNA secondary and tertiary structures.3

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Section: Single Qrrms Of Hnrnp F Regulate the Splicing Of Bcl-xmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs

Dominguez

Fisette

Chabot

et al. 2010

Nat Struct Mol Biol

Self Cite

140

174

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show abstract

“…Its overexpression was observed in primary carcinomas and metastases [48]; a downregulation of the protein and an increase of its fragmentation could be the result of drug treatments leading to the inhibition of cell proliferation and colony formation. Moreover, the overexpression of heterogeneous nuclear ribonucleoprotein H leads to production in HeLa cells of a proapoptotic alternative splice variant of Bcl-x [Blc-x(S)] [49]. At the time point of the Auoxo6 and auranofin treatments studied, no increased apoptosis was observed.…”

Section: Functional Roles Of the Identified Proteinsmentioning

confidence: 99%

Exploring the biochemical mechanisms of cytotoxic gold compounds: a proteomic study

et al. 2010

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We have recently shown that a group of structurally diverse gold compounds are highly cytotoxic toward a panel of 36 human tumor cell lines through a variety of biochemical mechanisms. A classic proteomic approach is exploited here to gain deeper insight into those mechanisms. This investigation is focused on Auoxo6, a novel binuclear gold(III) complex, and auranofin, a clinically established gold(I) antiarthritic drug. First, the 72-h cytotoxicity profiles of Auoxo6 and auranofin were determined against A2780 human ovarian carcinoma cells. Subsequently, protein extraction from gold-treated A2780 cells sensitive to cisplatin and 2D gel electrophoresis separation were carried out according to established procedures. Notably, both metallodrugs caused relatively modest changes in protein expression in comparison with controls as only 11 out of approximately 1,300 monitored spots showed appreciable quantitative changes. Very remarkably, six altered proteins were in common between the two treatments. Eight altered proteins were identified by mass spectrometry; among them was ezrin, a protein associated with the cytoskeleton and involved in apoptosis. Interestingly, two altered proteins, i.e., peroxiredoxins 1 and 6, are known to play crucial roles in the cell redox metabolism. Increased cleavage of heterogeneous ribonucleoprotein H was also evidenced, consistent with caspase 3 activation. Overall, the results of the present proteomic study point out that the mode of action of Auoxo6 is strictly related to that of auranofin, that the induced changes in protein expression are limited and selective, that both gold compounds trigger caspase 3 activation and apoptosis, and that a few affected proteins are primarily involved in cell redox homeostasis.

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