Genomic structure and functional characterization of the human ADAM10 promoter

Prinzen, Claudia; Müller, Ulrich; Endres, Kristina; Fahrenholz, Falk; Postina, Rolf

doi:10.1096/fj.04-3619fje

Cited by 121 publications

(135 citation statements)

References 64 publications

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“…Specifically, retinoic acid enhances ADAM10 transcription by promoting the binding of a non-permissive dimer of retinoic acid receptor-␣ and retinoid X receptor-␤ to retinoic acid-respon- sive elements in the promoter of the ADAM10 gene (57,58). ADAM10 transcription is also regulated by PAX2 in renal cancer cells (59) and melanocytes (60).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

Cheng

Zhang

et al. 2013

Journal of Biological Chemistry

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Background: MicroRNA (miR) dysregulation is found in Alzheimer disease (AD). A disintegrin and metalloprotease 10 (ADAM10) prevents generation of amyloid ␤ (A␤) and decrease AD pathology. Results: miR-144 suppresses ADAM10 expression and is up-regulated by activator protein-1. Conclusion: miR-144 is a negative regulator of ADAM10 and may be involved in AD pathogenesis. Significance:The first work to demonstrate the function of miRNA-144 and its regulation in the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

Cheng

Zhang

et al. 2013

Journal of Biological Chemistry

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“…The SK-N-MC cell line, stably expressing a firefly luciferase ADAM10 promoter reporter construct, was prepared as previously described [30].…”

Section: Detection Of Adam10 Promoter-driven Luciferase Activitymentioning

confidence: 99%

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

Kojro

Füger

Prinzen

et al. 2010

JAD

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Abstract. Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-β protein precursor (AβPP) and are reported to stimulate the activity of α-secretase, the major preventive secretase of Alzheimer's disease. Statins can increase the α-secretase activity by their cholesterol-lowering properties as well as by impairment of isoprenoids synthesis. In the present study, we elucidate the contribution of these pathways in α-secretase activation. We demonstrate that zaragozic acid, a potent inhibitor of squalene synthase which blocks cholesterol synthesis but allows synthesis of isoprenoids, also stimulates α-secretase activity. Treatment of human neuroblastoma cells with 50 µM zaragozic acid resulted in a ∼3 fold increase of α-secretase activity and reduced cellular cholesterol by ∼30%. These effects were comparable to results obtained from cells treated with a low lovastatin concentration (2 µM). Zaragozic acid-stimulated secretion of α-secretase cleaved soluble AβPP was dose dependent and saturable. Lovastatin-or zaragozic acid-stimulated increase of α-secretase activity was completely abolished by a selective ADAM10 inhibitor. By targeting the α-secretase ADAM10 to lipid raft domains via a glycosylphosphatidylinositol anchor, we demonstrate that ADAM10 is unable to cleave AβPP in a cholesterol-rich environment. Our results indicate that inhibition of cholesterol biosynthesis by a low lovastatin concentration is sufficient for α-secretase activation.

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“…ADAM10 is a multidomain transmembrane glycoprotein which is expressed ubiquitously (6). It contains an N-terminal signal sequence followed by a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich region, an EGFlike repeat, a transmembrane domain and a SH3-binding cytoplasmic tail (7).…”

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confidence: 99%

An Arginine Stretch Limits ADAM10 Exit from the Endoplasmic Reticulum

Marcello

Gardoni

Luca

et al. 2010

Journal of Biological Chemistry

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A disintegrin and metalloproteinase 10 (ADAM10) is a type I transmembrane glycoprotein responsible for the ectodomain shedding of a number of proteins implicated in the pathogenesis of diseases ranging from cancer to Alzheimer Disease. ADAM10 is synthesized in an inactive form, which is proteolytically activated during its forward transport along the secretory pathway and at the plasma membrane. Therefore, modulation of its trafficking could provide a mechanism to finely tune its shedding activity. Here we report the identification of an endoplasmic reticulum (ER) retention motif within the ADAM10 intracellular C-terminal tail. Sequential deletion/mutagenesis analyses showed that an arginine-rich ( 723 RRR) sequence was responsible for the retention of ADAM10 in the ER and its inefficient surface trafficking. Mutating the second arginine to alanine was sufficient to allow ER exit and surface expression in both heterologous cells and hippocampal neurons. As synapse-associated protein 97 (SAP97) binds ADAM10 at its cytoplasmic tail and facilitates forward ADAM10 trafficking in neurons, we tested whether SAP97 could modulate ER export. However, neither expression nor Ser-39 phosphorylation of SAP97 in heterologous cells or hippocampal neurons were sufficient to allow the ER exit of ADAM10, suggesting that other signaling pathways or alternative binding partners are responsible for ADAM10 ER exit. Together, these results identify a novel mechanism regulating the intracellular trafficking and membrane delivery of ADAM10.A disintegrin and metalloproteinase 10 (ADAM10) 2 belongs to a large family of membrane-anchored metalloproteases, which are known as the ADAM protein family. ADAMs mediate the proteolytic cleavage of transmembrane proteins in their juxtamembrane region, causing their shedding, i.e. the release of their extracellular domain in a soluble form. In addition, through the intracellularly retained stubs, ADAMs can initiate the activation of intracellular signaling cascades. Because of their metalloprotease, integrin binding, cell adhesion, and signaling functions, ADAMs are well positioned to coordinate cellular processes that are required for neural development, plasticity, and repair (1-3).ADAM10 works as a sheddase for a large number of transmembrane proteins involved in a variety of biological functions, and has been implicated in the pathogenesis of diseases ranging from cancer to Alzheimer Disease (AD) (4, 5). Because of these links, much effort is currently directed toward developing tools which modulate ADAM10 activity and can be used to target these pathologies.ADAM10 is a multidomain transmembrane glycoprotein which is expressed ubiquitously (6). It contains an N-terminal signal sequence followed by a prodomain, a metalloprotease domain, a disintegrin domain, a cysteine-rich region, an EGFlike repeat, a transmembrane domain and a SH3-binding cytoplasmic tail (7). ADAM10 is synthesized in an inactive form that carries a proprotein convertase (PC) recognition sequence between the prodomain and the c...

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Genomic structure and functional characterization of the human ADAM10 promoter

Cited by 121 publications

References 64 publications

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

An Arginine Stretch Limits ADAM10 Exit from the Endoplasmic Reticulum

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