A novel splicing regulator shares a nuclear import pathway with SR proteins

Lai, Ming‐Wei; Kuo, Hao-Wei; Chang, Wen‐Cheng; Tarn, Woan‐Yuh

doi:10.1093/emboj/cdg126

Cited by 99 publications

(140 citation statements)

References 42 publications

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“…Upon nuclear import, RBM4 is transiently colocalized with SR proteins in nuclear speckles (17). This study shows that cell stress-mediated signaling caused RBM4 accumulation in the cytoplasm and targeting to SGs, further suggesting dynamic localization of RBM4 even under the control of cellular signaling.…”

Section: Discussionmentioning

confidence: 55%

“…RBM4 primarily localizes to the nucleus with higher concentration in nucleoli and continuously shuttles between the nucleus and the cytoplasm (17). Upon nuclear import, RBM4 is transiently colocalized with SR proteins in nuclear speckles (17).…”

Section: Discussionmentioning

confidence: 99%

“…RNA-binding motif protein 4 (RBM4) is ubiquitously expressed with higher abundance in heart and muscle (17). RBM4 acts as a precursor mRNA splicing regulatory factor and can modulate cell type-specific exon selection of ␣-tropomyosin by binding to intronic CU-rich elements (18).…”

mentioning

confidence: 99%

“…It functionally antagonizes the activity of polypyrimidine tract-binding protein (PTB) by competing for overlapping cis-elements to determine ␣-tropomyosin exon selection. Moreover, RBM4 is a nucleocytoplasmic shuttling protein (17), but its cytoplasmic function was not determined.…”

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confidence: 99%

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Cell stress modulates the function of splicing regulatory protein RBM4 in translation control

Lin

Hsu

Tarn

2007

Proc. Natl. Acad. Sci. U.S.A.

117

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RNA-binding motif protein 4 (RBM4) plays a regulatory role in alternative splicing of precursor mRNA. We show here that cell stress such as arsenite exposure induces phosphorylation of RBM4 at serine 309 and also drives its cytoplasmic accumulation and targeting to stress granule via the MKK 3/6-p38 signaling pathway. Accordingly, RBM4 suppresses cap-dependent translation in a cis-element-dependent manner. However, RBM4 concomitantly activates internal ribosome entry site (IRES)-mediated translation likely by promoting the association of translation initiation factor eIF4A with IRES-containing mRNAs. Overexpression of RBM4 therefore mimics the effect of cell stress-induced signaling on translation initiation control. Whereas arsenite treatment promotes RBM4 loading onto IRES mRNAs and enhances RBM4 -eIF4A interactions, a nonphosphorylatable mutant of RBM4 was unresponsive to arsenite stress and failed to activate IRES-mediated translation. Thus, our results uncover a previously unrecognized paradigm for the RNA-binding protein RBM4 in its phosphorylation-modulated dual action as a suppressor of cap-dependent and enhancer of IRES-mediated translation in response to stress signals.cell stress ͉ eIF4A ͉ internal ribosome entry site ͉ phosphorylation ͉ splicing factor P osttranscriptional control of eukaryotic gene expression comprises several levels of regulation such as processing, export, turnover, localization, and translation of mRNAs (1). Each regulation step involves various combinations of RNAbinding proteins that form dynamic messenger ribonucleoproteins with the transcript. These messenger ribonucleoproteins may individually play specific roles in mRNA metabolism by forming distinct regulatory complexes (2). Some of them continuously shuttle between the nucleus and cytoplasm and may thus participate in multiple steps of mRNA metabolism in different subcellular compartments. For example, nuclear precursor mRNA splicing factors serine/arginine-rich (SR) proteins were recently implicated in several postsplicing activities including mRNA export, quality control, and translation (1, 3-5).Cellular signaling pathways may relocate messenger ribonucleoproteins and thereby modulate their function. For example, environmental stimuli such as osmotic shock induce phosphorylation and cytoplasmic accumulation of heterogeneous nuclear ribonucleoprotein (hnRNP) A1 via the MAPK pathway and hence alter its activity in splicing regulation (6, 7). Activation of the ERK signaling pathway can drive cytoplasmic accumulation of hnRNP K; blockade of this pathway attenuates the ability of hnRNP K to inhibit translation (8).The cellular response to environmental stress immediately leads to global repression of protein synthesis and aggregation of stalled translation complexes in cytoplasmic foci termed stress granules (SGs) (9, 10). However, stress-induced attenuation of global translation is also accompanied by selective translation of mRNAs that possess internal ribosome entry sites (IRES) (11,12). In particular, IRES-mediated tran...

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cell stress modulates the function of splicing regulatory protein RBM4 in translation control

Lin

Hsu

Tarn

2007

Proc. Natl. Acad. Sci. U.S.A.

117

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“…This strategy allowed the isolation of an isoform of coactivator-associated arginine methyltransferase 1 (CARM1), along with known splicing regulators Fox-1 (11), HRNBP2, and RBM4 (12). CARM1 has been shown to act as a transcriptional coactivator and cooperate synergistically with p300/CBP and p160 coactivators to enhance transcriptional activation by nuclear receptors (13).…”

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confidence: 99%

Coactivator-associated Arginine Methyltransferase 1, CARM1, Affects Pre-mRNA Splicing in an Isoform-specific Manner*♦

Ohkura¹,

Takahashi²,

Yaguchi³

et al. 2005

Journal of Biological Chemistry

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Molecular diversity through alternative splicing is important for cellular function and development. However, little is known about the factors that regulate alternative splicing. Here we demonstrate that one isoform of coactivator-associated arginine methyltransferase 1 (named CARM1-v3) associates with the U1 small nuclear RNP-specific protein U1C and affects 5 splice site selection of the pre-mRNA splicing. CARM1-v3 was generated by the retention of introns 15 and 16 of the primary transcript of CARM1. Its deduced protein lacks the C-terminal domain of the major isoform of CARM1 and instead has v3-specific sequences at the C terminus. CARM1-v3, but not the other isoforms, strongly stimulates a shift to the distal 5 splice site of the pre-mRNA when the adenoviral E1A minigene is used as a reporter and enhances the exon skips in the CD44 reporter. A CARM1-v3 mutant lacking the v3-specific sequences completely lost the ability to regulate the alternative splicing patterns. In addition, CARM1-v3 shows tissuespecific expression patterns distinct from those of the other isoforms. These results suggest that the transcriptional coactivator can affect the splice site decision in an isoform-specific manner.It has been estimated that about 60% of human genes undergo alternative splicing (1). Commonly, alternative splicing determines the inclusion of a portion of coding sequence in the mRNA, giving rise to protein isoforms that differ in their peptide sequence and hence chemical and biological activity. The mechanism of alternative splicing permits diversity of translatable mRNAs, thereby increasing the proteome diversity encoded by a limited number of genes. Genetic switches based on alternative splicing are known to be important in many cellular and developmental processes, including sex determination, apoptosis, axon guidance, and tissue-specific differentiation (2-4).Although a large variety of splicing decisions can be explained by the antagonistic effects of general splicing factors, such as serine/arginine-rich proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), 1 it is most likely that tissue-specific or developmentally regulated splicing factors have an important role in the regulation of alternative splicing. In Drosophila melanogaster, sex-lethal functions as a regulator of alternative splicing in sex determination (2), and the embryonic lethal abnormal visual system is a gene-specific regulator of alternative pre-mRNA processing in neurons (3). However, in mammals, only a limited number of splicing regulators have been identified to date, despite the large diversity of the mammalian gene transcripts, and little is known about the mechanisms by which alternative splicing is regulated.Pre-mRNA splicing occurs in a large multicomponent ribonucleoprotein complex called the spliceosome, which is composed of U1, U2, U4/U6, and U5 small nuclear ribonucleoprotein (snRNP) particles and many non-snRNP protein splicing factors (5). U1 snRNP recognizes the 5Ј splice site and is among the first factors to inter...

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