Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region

Mihailovich, Marija; Thermann, Rolf; Grohovaz, Fabio; Hentze, Matthias W.; Zacchetti, Daniele

doi:10.1093/nar/gkm191

Cited by 57 publications

(73 citation statements)

References 58 publications

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“…One could surmise that these genes are post-transcriptionally regulated to avoid the excess protein that is associated with cytotoxicity and disease. Previous independent studies have reported post-transcriptional regulation for BACE1 (Lammich et al 2004;Mihailovich et al 2007;Hebert et al 2008) and APP Venti et al 2004;Patel et al 2008), in agreement with our data. Fifteen genes were post-transcriptionally up-regulated in at least two cell lines, and GSEA analysis revealed an enrichment for genes that respond to external signals such as viral infection (P = 5.37 3 10 À5 ), and interferon-alpha (P = 1.8 3…”

Section: à5supporting

confidence: 93%

Transcriptional and post-transcriptional profile of human chromosome 21

Nikolaev¹,

Deutsch²,

Genolet³

et al. 2009

Genome Res.

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Recent studies have demonstrated extensive transcriptional activity across the human genome, a substantial fraction of which is not associated with any functional annotation. However, very little is known regarding the post-transcriptional processes that operate within the different classes of RNA molecules. To characterize the post-transcriptional properties of expressed sequences from human chromosome 21 (HSA21), we separated RNA molecules from three cell lines (GM06990, HeLa S3, and SK-N-AS) according to their ribosome content by sucrose gradient fractionation. Polyribosomal-associated RNA and total RNA were subsequently hybridized to genomic tiling arrays. We found that ;50% of the transcriptional signals were located outside of annotated exons and were considered as TARs (transcriptionally active regions). Although TARs were observed among polysome-associated RNAs, RT-PCR and RACE experiments revealed that ;40% were likely to represent nonspecific cross-hybridization artifacts. Bioinformatics discrimination of TARs according to conservation and sequence complexity allowed us to identify a set of high-confidence TARs. This set of TARs was significantly depleted in the polysomes, suggesting that it was not likely to be involved in translation. Analysis of polysome representation of RefSeq exons showed that at least 15% of RefSeq transcripts undergo significant post-transcriptional regulation in at least two of the three cell lines tested. Among the regulated transcripts, enrichment analysis revealed an over-representation of genes involved in Alzheimer's disease (AD), including APP and the BACE1 protease that cleaves APP to produce the pathogenic beta 42 peptide. We demonstrate that the combination of RNA fractionation and tiling arrays is a powerful method to assess the transcriptional and post-transcriptional properties of genomic regions.

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Section: à5supporting

confidence: 93%

Transcriptional and post-transcriptional profile of human chromosome 21

Nikolaev¹,

Deutsch²,

Genolet³

et al. 2009

Genome Res.

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“…Previous studies have supported a role for miRNAs in biologically important partial, as opposed to complete, suppression of target mRNAs (Sevignani et al, 2006;Li et al, 2007). BACE1 genetic regulation is complex (Preece et al, 2003;Lahiri et al, 2006;Li et al, 2006;Rossner et al, 2006;Mihailovich et al, 2007;Stockley and O'Neill, 2007;Tesco et al, 2007) and has been shown to occur partly posttranscriptionally (Marambaud et al, 1998;Rossner et al, 2006). Different regulatory mechanisms probably overlap in time and in cytoplasmic domains with multiple transcriptional, translational, and posttranslational processes involved in BACE1 regulation.…”

Section: Non-demented-case1mentioning

confidence: 94%

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

Wang¹,

Rajeev²,

Stromberg³

et al. 2008

J. Neurosci.

743

605

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MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3Ј-untranslated region (UTR) of ␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3Ј-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1.

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“…analysis revealed that the ADAM10 mRNA contains a long 5Ј-UTR with similar properties as the 5Ј-UTR of BACE1, which was shown to be involved in translational repression of BACE1 (32)(33)(34)(35)(36). The 5Ј-UTR of ADAM10 was cloned from a human macrophage cDNA library (41) and contains 444 nucleotides, has a high GC content (69%), and has two uORFs.…”

Section: Adam10 Transcripts Contain a Gc-rich 5ј-utr-sequencementioning

confidence: 99%

“…Among these, BACE1 protein expression was shown to be significantly repressed by its 5Ј-UTR (32)(33)(34)(35)(36). It was demonstrated that the GC-rich region within the BACE1 5Ј-UTR forms a translational barrier that may impede scanning of the ribosome along the 5Ј-UTR or initiate translation (34).…”

mentioning

confidence: 99%

“…It was demonstrated that the GC-rich region within the BACE1 5Ј-UTR forms a translational barrier that may impede scanning of the ribosome along the 5Ј-UTR or initiate translation (34). Moreover, translation of an upstream open reading frame (uORF) in the 5Ј-UTR was shown to be involved in translational repression of BACE1 (35,36). Recently, it was demonstrated that under stress conditions the translation preinitiation complex bypasses this uORF and structured regions in the 5Ј-UTR of BACE1, which leads to increased BACE1 translation (37).…”

mentioning

confidence: 99%

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Expression of the Anti-amyloidogenic Secretase ADAM10 Is Suppressed by Its 5′-Untranslated Region

Lammich

Buell

Zilow

et al. 2010

Journal of Biological Chemistry

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Proteolytic processing of the amyloid precursor protein by ␣-secretase prevents formation of the amyloid ␤-peptide (A␤), which is the main constituent of amyloid plaques in brains of Alzheimer disease (AD) patients. ␣-Secretase activity is decreased in AD, and overexpression of the ␣-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology. ADAM10 has a 444-nucleotide-long, very GC-rich 5-untranslated region (5-UTR) with two upstream open reading frames. Because similar properties of 5-UTRs are found in transcripts of many genes, which are regulated by translational control mechanisms, we asked whether ADAM10 expression is translationally controlled by its 5-UTR. We demonstrate that the 5-UTR of ADAM10 represses the rate of ADAM10 translation. In the absence of the 5-UTR, we observed a significant increase of ADAM10 protein levels in HEK293 cells, whereas mRNA levels were not changed. Moreover, the 5-UTR of ADAM10 inhibits translation of a luciferase reporter in an in vitro transcription/translation assay. Successive deletion of the first half of the ADAM10 5-UTR revealed a striking increase in ADAM10 protein expression in HEK293 cells, suggesting that this part of the 5-UTR contains inhibitory elements for translation. Moreover, we detect an enhanced ␣-secretase activity and consequently reduced A␤ levels in the conditioned medium of HEK293 cells expressing both amyloid precursor protein and a 5-UTR-ADAM10 deletion construct lacking the first half of the 5-UTR. Thus, we provide evidence that the 5-UTR of ADAM10 may have an important role for post-transcriptional regulation of ADAM10 expression and consequently A␤ production. Alzheimer disease (AD)4 is the most common form of dementia worldwide. The major pathological hallmarks of AD are neurofibrillary tangles and amyloid plaques (1). Amyloid plaques are composed of the amyloid-␤ peptide (A␤), which is derived by proteolysis from the ␤-amyloid precursor protein (APP) (2). Two proteases, termed ␤-and ␥-secretase generate A␤. The aspartyl protease ␤-site APP cleaving enzyme 1 (BACE1) was identified as ␤-secretase and cleaves APP into two fragments (summarized in Ref.3). The extracellular N-terminal domain of APP, APPs␤, is released upon shedding by BACE1. Recently, it was reported that a N-terminal proteolytic derivative of APPs␤ could bind to the death receptor DR6, thereby triggering axon pruning and neuronal death under conditions where trophic factors are reduced (4). The remaining membrane-bound C-terminal stub of APP is the immediate precursor for A␤ generation by ␥-secretase (5). Alternatively, APP is also cleaved in a nonamyloidogenic pathway by ␣-secretase within the A␤ domain, thereby preventing the formation of A␤ (6, 7). Processing of APP by ␣-secretase generates the soluble APPs␣ ectodomain, which may have neuroprotective and neurotrophic properties (8). The resulting membrane-bound C-terminal fragment is further cleaved by ␥-secretase to produce p3, a N-terminally truncated A␤ derivative (9).Three memb...

show abstract

Complex translational regulation of BACE1 involves upstream AUGs and stimulatory elements within the 5' untranslated region

Cited by 57 publications

References 58 publications

Transcriptional and post-transcriptional profile of human chromosome 21

Transcriptional and post-transcriptional profile of human chromosome 21

The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1

Expression of the Anti-amyloidogenic Secretase ADAM10 Is Suppressed by Its 5′-Untranslated Region

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