Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site

Damiano, Fabrizio; Alemanno, Simone; Gnoni, Gabriele V.; Siculella, Luisa

doi:10.1042/bj20091827

Cited by 64 publications

(57 citation statements)

References 49 publications

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“…The HEM25 open reading frame was amplified from S. cerevisiae genomic DNA by PCR using primers corresponding to the extremities of the coding sequences with additional NdeI and HindIII sites (5Ј-AAGCTTCATATGACTGAGCAAGCAAC-TAA-3Ј as the forward primer and 5Ј-GAATTCAAGCTTGA-ATCTTTTGACCAACTCCT-3Ј as the reverse primer, respectively). The coding sequence of the human SLC25A38 gene was obtained by RT-PCR reaction using total RNA extracted from HepG2 cells as template (44,45) and the primers with additional NdeI and HindIII sites (5Ј-AAGCTTCATATGAT-TCAGAACTCACGTCC-3Ј and 5Ј-GAATTCAAGCTTGGA-CTTCAGGCCCATCTTGG-3Ј, respectively). The amplified products were cloned into the NdeI-HindIII sites of the expression vector pET21b that had been previously modified by cloning into HindIII-XhoI sites a cDNA sequence coding for a V5 epitope followed by six histidines (46).…”

Section: Methodsmentioning

confidence: 99%

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

Lunetti

Damiano

Benedetto

et al. 2016

Journal of Biological Chemistry

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Heme is an essential molecule in many biological processes, such as transport and storage of oxygen and electron transfer as well as a structural component of hemoproteins. Defects of heme biosynthesis in developing erythroblasts have profound medical implications, as represented by sideroblastic anemia. The synthesis of heme requires the uptake of glycine into the mitochondrial matrix where glycine is condensed with succinyl coenzyme A to yield ␦-aminolevulinic acid. Herein we describe the biochemical and molecular characterization of yeast Hem25p and human SLC25A38, providing evidence that they are mitochondrial carriers for glycine. In particular, the hem25⌬ mutant manifests a defect in the biosynthesis of ␦-aminolevulinic acid and displays reduced levels of downstream heme and mitochondrial cytochromes. The observed defects are rescued by complementation with yeast HEM25 or human SLC25A38 genes. Our results identify new proteins in the heme biosynthetic pathway and demonstrate that Hem25p and its human orthologue SLC25A38 are the main mitochondrial glycine transporters required for heme synthesis, providing definitive evidence of their previously proposed glycine transport function. Furthermore, our work may suggest new therapeutic approaches for the treatment of congenital sideroblastic anemia.

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Section: Methodsmentioning

confidence: 99%

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

Lunetti

Damiano

Benedetto

et al. 2016

Journal of Biological Chemistry

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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

505

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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“…14,15 Interestingly, SREBP-1 contains an internal ribosome entry site, allowing its translation despite the overall reduction in protein synthesis. 16 Although ER stress may activate SREBP and was implicated in AngII-induced cardiac pathology, [17][18][19] whether AngII induces ER stress in MCs and the kidney is unknown.…”

mentioning

confidence: 99%

SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis

Wang

Chen

et al. 2015

Journal of the American Society of Nephrology

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Angiotensin II is an important mediator of CKD of diverse etiology. A common pathologic feature of CKD is glomerular fibrosis, a central mediator of which is the profibrotic cytokine TGF-b. The mechanisms underlying the induction of TGF-b and matrix by angiotensin II are not completely understood. Recent studies showed that overexpression of the transcription factor SREBP-1 induces glomerular sclerosis and that angiotensin II can activate SREBP-1 in tubular cells. We thus studied whether SREBP-1 is activated by angiotensin II and mediates angiotensin II-induced profibrogenic responses in primary rat mesangial cells. Treatment of cells with angiotensin II induced the upregulation and activation of SREBP-1. Angiotensin II-induced activation of SREBP-1 required signaling through the angiotensin II type I receptor and activation of PI3K/Akt in addition to the chaperone SCAP and protease S1P. Notably, angiotensin II-induced endoplasmic reticulum stress was identified as a key mediator of Akt-SREBP-1 activation, and inhibition of endoplasmic reticulum stress or SREBP-1 prevented angiotensin II-induced SREBP-1 binding to the TGF-b promoter, TGF-b upregulation, and downstream fibronectin upregulation. Endoplasmic reticulum stress alone, however, did not induce TGF-b upregulation despite activating SREBP-1. Although not required for SREBP-1 activation by angiotensin II, EGF receptor signaling was necessary for activation of the SREBP-1 cotranscription factor Sp1, which provided a required second signal for TGF-b upregulation. In vivo, endoplasmic reticulum stress and SREBP-1-dependent effects were induced in glomeruli of angiotensin II-infused mice, and administration of the SREBP inhibitor fatostatin prevented angiotensin II-induced TGF-b upregulation and matrix accumulation. SREBP-1 and endoplasmic reticulum stress thus provide potential novel therapeutic targets for the treatment of CKD.

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Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site

Cited by 64 publications

References 49 publications

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

Characterization of Human and Yeast Mitochondrial Glycine Carriers with Implications for Heme Biosynthesis and Anemia

The role of ER stress in lipid metabolism and lipotoxicity

SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis

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