hnRNP A1 mediates the activation of the IRES-dependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress

Damiano, Fabrizio; Rochira, Alessio; Tocci, Romina; Alemanno, Simone; Gnoni, Antonio; Siculella, Luisa

doi:10.1042/bj20120906

Cited by 49 publications

(34 citation statements)

References 56 publications

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“…Prior work also supports ERK/p38MAPK pathways and IRES stimulation as protective responses to ER stress (22–24). Our work identifies MNK1 activity as the probable link between upstream MAPK pathway activation and IRES upregulation.…”

Section: Discussionmentioning

confidence: 81%

RETRACTED ARTICLE: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

Shi¹,

Yang²,

Hoang³

et al. 2015

Oncogene

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Protein translation is inhibited by the unfolded protein response (UPR)-induced eIF-2α phosphorylation to protect against endoplasmic reticulum (ER) stress. In addition, we found additional inhibition of protein translation due to diminished mTORC1 activity in ER-stressed multiple myeloma (MM) cells. However, c-myc protein levels and myc translation was maintained. To ascertain how c-myc was maintained, we studied myc IRES function which does not require mTORC1 activity. Myc IRES activity was upregulated in MM cells during ER stress induced by thapsigargin, tunicamycin or the myeloma therapeutic bortezomib. IRES activity was dependent upon upstream MAPK and MNK1 signaling. A screen identified hnRNP A1 (A1) and RPS 25 as IRES-binding trans factors required for ER stress-activated activity. A1 associated with RPS25 during ER stress and this was prevented by a MNK inhibitor. In a proof of principle, we identified a compound that prevented binding of A1 to the myc IRES and specifically inhibited myc IRES activity in MM cells. This compound, when used alone, was not cytotoxic nor did it inhibit myc translation or protein expression. However, when combined with ER stress inducers, especially bortezomib, a remarkable synergistic cytotoxicity ensued with associated inhibition of myc translation and expression. These results underscore the potential for targeting A1-mediated myc IRES activity in MM cells during ER stress.

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Section: Discussionmentioning

confidence: 81%

RETRACTED ARTICLE: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

Shi¹,

Yang²,

Hoang³

et al. 2015

Oncogene

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“…In cap-independent translation systems, hnRNP A1 has been shown to bind internal ribosomal entry site (IRESs) sequences, which govern cap-independent translation initiation in cellular and viral mRNAs [146]. The assembly of hnRNP A1 onto IRESs has been shown to enhance IRES-mediated translation of the human fibroblast growth factor 2 (FGF-2) mRNA [147], the human rhinovirus (HRV) [148] and, more recently, the transcription factor, SREBP-1 (sterol-regulatory-element-binding protein 1) in hepatocytes [149]. Studies on the expression of the cyclin D1 and c-myc mRNAs show that hnRNP A1 constitutively binds and promotes translation from the IRES of both genes, and this activity is negatively modulated by phosphorylation of hnRNP A1 by the Akt kinase [150,151].…”

Section: Hnrnp A1 Regulates Mrna Translation and Turnovermentioning

confidence: 99%

hnRNP A1: The Swiss Army Knife of Gene Expression

Jean-Philippe

Paz

Caputi

2013

IJMS

259

262

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Eukaryotic cells express a large variety of RNA binding proteins (RBPs), with diverse affinities and specificities towards target RNAs. These proteins play a crucial role in almost every aspect of RNA biogenesis, expression and function. The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a complex and diverse family of RNA binding proteins. hnRNPs display multiple functions in the processing of heterogeneous nuclear RNAs into mature messenger RNAs. hnRNP A1 is one of the most abundant and ubiquitously expressed members of this protein family. hnRNP A1 plays multiple roles in gene expression by regulating major steps in the processing of nascent RNA transcripts. The transcription, splicing, stability, export through nuclear pores and translation of cellular and viral transcripts are all mechanisms modulated by this protein. The diverse functions played by hnRNP A1 are not limited to mRNA biogenesis, but extend to the processing of microRNAs, telomere maintenance and the regulation of transcription factor activity. Genomic approaches have recently uncovered the extent of hnRNP A1 roles in the development and differentiation of living organisms. The aim of this review is to highlight recent developments in the study of this protein and to describe its functions in cellular and viral gene expression and its role in human pathologies.

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“…Pharmacologically induced ER stress in HepG2 cells increased the expression of SREBP-1c via cap-independent internal translation of SREBP-1c mRNA by hnRNP-A1 (103,104), which in turn activated fatty acid synthesis in L02 cells (105). ER stress also induced hepatic steatosis via increased expression of hepatic VLDL receptor (VLDLR) through direct binding of the ATF4 transcription factor to the VLDLR promoter region leading to accumulation of TG (106).…”

Section: Er Stress and Lipotoxicity In Peripheral Organsmentioning

confidence: 99%

The role of ER stress in lipid metabolism and lipotoxicity

Han

Kaufman

2016

Journal of Lipid Research

502

372

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extremely high Ca 2+ concentration (1), which is maintained by the active transport function of the sarco/ER calcium ATPase (SERCA) (2). Many ER chaperone proteins and enzymes depend on higher Ca 2+ levels to facilitate protein folding and maturation (3). Therefore, maintaining ER homeostasis is essential for proper protein production and cell function. Homeostasis in the ER is disrupted by a number of insults, including pharmacological perturbation, genetic mutation of ER chaperones or their client proteins, elevated expression of proteins that transit the endomembrane system, viral infection, alterations in Ca 2+ or redox status, and limited or excessive available nutrients such as lipids. The accumulation of unfolded or misfolded proteins in the ER lumen activates a set of intracellular signaling pathways known as the unfolded protein response (UPR) (4, 5). The UPR regulates the quantity of ER driven by synthesis of lipids (6) and protein components of the ER to accommodate fluctuating demands on protein folding and other ER functions in response to different physiological and pathological conditions.The ER is also the major site for the synthesis of sterols and phospholipids that constitute the bulk of the lipid components of all biological membranes. In addition, many enzymes and regulatory proteins involved in lipid metabolism reside in the ER. The ER, therefore, plays an essential role in controlling membrane lipid composition (7) and membrane lipid homeostasis in all cell types. Fat The endoplasmic reticulum (ER) is a central organelle where proteins destined for the cell surface and the endomembrane system enter the secretory pathway. Once inside the ER lumen, newly synthesized polypeptides fold into their three-dimensional structures, assemble into higher order multimeric complexes, and are subject to posttranslational modifications such as glycosylation, hydroxylation, lipidation, and disulfide formation. The ER contains an Abbreviations: ACC, acetyl-CoA carboxylase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, immunoglobulin heavy-chain binding protein; CHOP, C/EBP homologous protein; eIF2, eukaryotic translation initiation factor 2; ER, endoplasmic reticulum; ERAD, ER-associated degradation; FXR, farnesoid X receptor; GADD34, growth arrest and DNA damage-inducible protein 34; HFD, high-fat diet; HFrD, high-fructose diet; IRE1, inositol-requiring enzyme 1; 4-PBA, 4-phenylbutyric acid; PERK, the double-stranded RNAactivated protein kinase-like eukaryotic initiation factor 2 kinase; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase 1; SERCA, sarco/ endoplasmic reticulum calcium ATPase; SFA, saturated fatty acid; S1P, serine protease site-1; S2P, metalloprotease site-2; SREBP, sterol regulatory element-binding protein; TUDCA, tauroursodeoxycholic acid; UPR, unfolded protein response; VLDLR, VLDL receptor; XBP1, X-box binding protein 1; Xbp1s, transcriptionally active form of X-box binding protein 1.

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hnRNP A1 mediates the activation of the IRES-dependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress

Cited by 49 publications

References 56 publications

RETRACTED ARTICLE: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

RETRACTED ARTICLE: Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

hnRNP A1: The Swiss Army Knife of Gene Expression

The role of ER stress in lipid metabolism and lipotoxicity

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