scholarly journals Cytoplasmic Relocalization of Heterogeneous Nuclear Ribonucleoprotein A1 Controls Translation Initiation of Specific mRNAs

2007 ◽  
Vol 18 (12) ◽  
pp. 5048-5059 ◽  
Author(s):  
Anne Cammas ◽  
Frédéric Pileur ◽  
Sophie Bonnal ◽  
Stephen M. Lewis ◽  
Nicolas Lévêque ◽  
...  
Keyword(s):  
Hnrnp A1 ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Mrna Metabolism ◽  
Direct Demonstration ◽  
Specific Mrnas ◽  
Regulate Protein ◽  
Nuclear Ribonucleoprotein ◽  
Mrna Binding

Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is a nucleocytoplasmic shuttling protein that regulates gene expression through its action on mRNA metabolism and translation. The cytoplasmic redistribution of hnRNP A1 is a regulated process during viral infection and cellular stress. Here, we show that hnRNP A1 is an internal ribosome entry site (IRES) trans-acting factor that binds specifically to the 5′ untranslated region of both the human rhinovirus-2 and the human apoptotic peptidase activating factor 1 (apaf-1) mRNAs, thereby regulating their translation. Furthermore, the cytoplasmic redistribution of hnRNP A1 after rhinovirus infection leads to enhanced rhinovirus IRES-mediated translation, whereas the cytoplasmic relocalization of hnRNP A1 after UVC irradiation limits the UVC-triggered translational activation of the apaf-1 IRES. Therefore, this study provides a direct demonstration that IRESs behave as translational enhancer elements regulated by specific trans-acting mRNA binding proteins in given physiological conditions. Our data highlight a new way to regulate protein synthesis in eukaryotes through the subcellular relocalization of a nuclear mRNA-binding protein.

scholarly journals Phosphomimetic Substitution of Heterogeneous Nuclear Ribonucleoprotein A1 at Serine 199 Abolishes AKT-dependent Internal Ribosome Entry Site-transacting Factor (ITAF) Function via Effects on Strand Annealing and Results in Mammalian Target of Rapamycin Complex 1 (mTORC1) Inhibitor Sensitivity

2011 ◽  
Vol 286 (18) ◽  
pp. 16402-16413 ◽  
Author(s):  
Jheralyn Martin ◽  
Janine Masri ◽  
Cheri Cloninger ◽  
Brent Holmes ◽  
Nicholas Artinian ◽  
...  
Keyword(s):  
Internal Ribosome Entry Site ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Hnrnp A1 ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Nuclear Ribonucleoprotein ◽  
Mtor Complex 1

The relative activity of the AKT kinase has been demonstrated to be a major determinant of sensitivity of tumor cells to mammalian target of rapamycin (mTOR) complex 1 inhibitors. Our previous studies have shown that the multifunctional RNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) A1 regulates a salvage pathway facilitating internal ribosome entry site (IRES)-dependent mRNA translation of critical cellular determinants in an AKT-dependent manner following mTOR inhibitor exposure. This pathway functions by stimulating IRES-dependent translation in cells with relatively quiescent AKT, resulting in resistance to rapamycin. However, the pathway is repressed in cells with elevated AKT activity, rendering them sensitive to rapamycin-induced G1 arrest as a result of the inhibition of global eIF-4E-mediated translation. AKT phosphorylation of hnRNP A1 at serine 199 has been demonstrated to inhibit IRES-mediated translation initiation. Here we describe a phosphomimetic mutant of hnRNP A1 (S199E) that is capable of binding both the cyclin D1 and c-MYC IRES RNAs in vitro but lacks nucleic acid annealing activity, resulting in inhibition of IRES function in dicistronic mRNA reporter assays. Utilizing cells in which AKT is conditionally active, we demonstrate that overexpression of this mutant renders quiescent AKT-containing cells sensitive to rapamycin in vitro and in xenografts. We also demonstrate that activated AKT is strongly correlated with elevated Ser(P)199-hnRNP A1 levels in a panel of 22 glioblastomas. These data demonstrate that the phosphorylation status of hnRNP A1 serine 199 regulates the AKT-dependent sensitivity of cells to rapamycin and functionally links IRES-transacting factor annealing activity to cellular responses to mTOR complex 1 inhibition.

scholarly journals hnRNP A1 Interacts with the 5′ Untranslated Regions of Enterovirus 71 and Sindbis Virus RNA and Is Required for Viral Replication

2009 ◽  
Vol 83 (12) ◽  
pp. 6106-6114 ◽  
Author(s):  
Jing-Yi Lin ◽  
Shin-Ru Shih ◽  
Manjing Pan ◽  
Carol Li ◽  
Chia-Fang Lue ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Sindbis Virus ◽  
Enterovirus 71 ◽  
Untranslated Regions ◽  
Hnrnp A1 ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Virus Rna ◽  
Infected Cells ◽  
Nuclear Ribonucleoprotein

ABSTRACT Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is involved in pre-mRNA splicing in the nucleus and translational regulation in the cytoplasm. The cytoplasmic redistribution of hnRNP A1 is a regulated process during viral infection and cellular stress. Here we demonstrate that hnRNP A1 not only is an internal ribosome entry site (IRES) trans-acting factor that binds specifically to the 5′ untranslated region (UTR) of enterovirus 71 (EV71) and regulates IRES-dependent translation but also binds to the 5′ UTR of Sindbis virus (SV) and facilitates its translation. The cytoplasmic relocalization of hnRNP A1 in EV71-infected cells leads to the enhancement of EV71 IRES-mediated translation, and its function can be substituted by hnRNP A2, whereas the cytoplasmic relocalization of hnRNP A1 following SV infection enhances the SV translation, but this function cannot be replaced by hnRNP A2. Our study provides the first direct evidence that the cytoplasmic relocalization of hnRNP A1 controls not only the IRES-dependent but also non-IRES-dependent translation initiations of RNA viruses.

scholarly journals hnRNP A1 Relocalization to the Stress Granules Reflects a Role in the Stress Response

2006 ◽  
Vol 26 (15) ◽  
pp. 5744-5758 ◽  
Author(s):  
Sonia Guil ◽  
Jennifer C. Long ◽  
Javier F. Cáceres
Keyword(s):  
Stress Response ◽  
Mammalian Cells ◽  
Stress Granules ◽  
Binding Activity ◽  
Hnrnp A1 ◽  
Mrna Metabolism ◽  
Discrete Phase ◽  
Cytoplasmic Accumulation ◽  
Mrna Binding

ABSTRACT hnRNP A1 is a nucleocytoplasmic shuttling protein that is involved in many aspects of mRNA metabolism. We have previously shown that activation of the p38 stress-signaling pathway in mammalian cells results in both hyperphosphorylation and cytoplasmic accumulation of hnRNP A1, affecting alternative splicing regulation in vivo. Here we show that the stress-induced cytoplasmic accumulation of hnRNP A1 occurs in discrete phase-dense particles, the cytoplasmic stress granules (SGs). Interestingly, mRNA-binding activity is required for both phosphorylation of hnRNP A1 and localization to SGs. We also show that these effects are mediated by the Mnk1/2 protein kinases that act downstream of p38. Finally, depletion of hnRNP A1 affects the recovery of cells from stress, suggesting a physiologically significant role for hnRNP A1 in the stress response. Our data are consistent with a model whereby hnRNP A1 recruitment to SGs involves Mnk1/2-dependent phosphorylation of mRNA-bound hnRNP A1.

scholarly journals Modulation of exon skipping and inclusion by heterogeneous nuclear ribonucleoprotein A1 and pre-mRNA splicing factor SF2/ASF

1993 ◽  
Vol 13 (5) ◽  
pp. 2993-3001
Author(s):  
A Mayeda ◽  
D M Helfman ◽  
A R Krainer
Keyword(s):  
Alternative Splicing ◽  
Splice Site ◽  
Exon Skipping ◽  
Splicing Factor ◽  
Alternative Exon ◽  
Hnrnp A1 ◽  
Exon Inclusion ◽  
Heterogeneous Nuclear Ribonucleoprotein ◽  
Nuclear Ribonucleoprotein

The essential splicing factor SF2/ASF and the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) modulate alternative splicing in vitro of pre-mRNAs that contain 5' splice sites of comparable strengths competing for a common 3' splice site. Using natural and model pre-mRNAs, we have examined whether the ratio of SF2/ASF to hnRNP A1 also regulates other modes of alternative splicing in vitro. We found that an excess of SF2/ASF effectively prevents inappropriate exon skipping and also influences the selection of mutually exclusive tissue-specific exons in natural beta-tropomyosin pre-mRNA. In contrast, an excess of hnRNP A1 does not cause inappropriate exon skipping in natural constitutively or alternatively spliced pre-mRNAs. Although hnRNP A1 can promote alternative exon skipping, this effect is not universal and is dependent, e.g., on the size of the internal alternative exon and on the strength of the polypyrimidine tract in the preceding intron. With appropriate alternative exons, an excess of SF2/ASF promotes exon inclusion, whereas an excess of hnRNP A1 causes exon skipping. We propose that in some cases the ratio of SF2/ASF to hnRNP A1 may play a role in regulating alternative splicing by exon inclusion or skipping through the antagonistic effects of these proteins on alternative splice site selection.

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