Identification of <i>cis</i>-Regulatory Sequences in the Human Angiotensinogen Gene by Transgene Coplacement and Site-Specific Recombination

Shimizu, Takumi; Oishi, Takayuki; Omori, Akane; Sugiura, Akiko; Hirota, Kaoru; Aoyama, Hisanori; Saito, Tomoko; Sugaya, Takeshi; Kon, Yasuhiro; Engel, James Douglas; Fukamizu, Akiyoshi; Tanimoto, Koichi

doi:10.1128/mcb.25.8.2938-2945.2005

Cited by 13 publications

(8 citation statements)

References 48 publications

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“…Activity of other sheddases is pH‐dependent. For instance, BACE1 has an acidic pH optimum (Vassar et al , ; Shimizu et al , ), thus only cleaving in acidic cellular compartments. Therefore, depending on the substrates’ localization, some BACE1 substrates are predominantly cleaved in endosomes, whereas others are mostly cleaved in the TGN.…”

Section: Cellular Localization Of Ectodomain Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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Section: Cellular Localization Of Ectodomain Sheddingmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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“…This approach was effectively done for the human angiotensinogen gene [44]. However, both the humanized CHGA strains displayed similar CHGA expression profiles mimicking mouse Chga expression, and we therefore conclude that no adverse gene disruption occurred as a result of BAC integration in both lines.…”

Section: Discussionmentioning

confidence: 66%

Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models

Mir

Zhang²,

Milic³

et al. 2016

Journal of Hypertension

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Objective The human prohormone chromogranin A (CHGA), an index member of the granin family is processed to generate catestatin, a peptide that is hypotensive in action and modulates catecholamine release within the sympathoadrenal system. Hypertensive patients with excess sympathetic activity have diminished catestatin. Often the study of physiological consequences of human genetic variation is confounded by elements such as other variations in obligatory linkage disequilibrium with the variant being studied. Also the phenotype of the variant may be influenced by genetic background that varies amongst individuals. This study addresses the effects of a human catestatin polymorphism (rs9658667) using humanized CHGA mouse models. Methods We created pertinent humanized mouse models wherein the mouse Chga gene locus was replaced by the human ortholog wild-type and the variant versions. This allowed for probing of the effects of catestatin variation in vivo with controls for other variations and global genetic background. Results Both the wild-type and variant human catestatin expressing mouse models were normotensive. The variant catestatin mouse model recapitulated physiological influence of the polymorphism on autonomic traits. These mice had diminished catecholamine, attenuated stress response and increased baroreceptor slopes that would suggest reduced risk of developing hypertension. Elevated plasma glucose, a trait observed in humans was not observed in mice expressing the variant catestatin. Conclusion This functional genomics approach of creating humanized mouse models to study rs9658667 polymorphism recapitulated and validated many of the human trait associations. This approach can also be applied in the study of other human gene polymorphisms.

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“…To facilitate cloning procedures, we replaced the XhoI-SacI portion of the pBluescript II KS (+) with double-stranded oligonucleotides containing XhoI-StuI-MscI-BclI restriction enzyme sites; hereafter, we refer to this modified plasmid as pBluescript II KAS (+). A floxed Kan r cassette was PCR amplified and digested with EcoRI and SacII, as described previously (23).…”

Section: Bac Clone and Mutagenesismentioning

confidence: 99%

“…Therefore, in order to compare the levels of Tg expression between WT and mutant (mut) loci, a large number of TgM lines must be analyzed. To overcome this problem, we adopted a combination of 2 technologies: BAC transgenesis and coplacement (23). BAC inserts (~200 kb) carry more genetic information than commonly used plasmids (~20 kb).…”

Section: Introductionmentioning

confidence: 99%

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A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

Tanimoto¹,

Sugiura²,

Kanafusa³

et al. 2008

J. Clin. Invest.

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Renin, a major regulatory component of the renin-angiotensin system, plays a pivotal role in regulating blood pressure and electrolyte homeostasis and is predominantly expressed in the kidney. Several cAMP-responsive elements have been identified within renin gene promoters. Here, we study how 2 such elements, renin proximal promoter element-2 (RP-2) and overlapping cAMP and negative regulatory elements (CNRE), affect the transcriptional regulation of renin. We generated Tg mice (TgM) bearing BACs containing either WT or mutant RP-2 or CNRE, integrated at single chromosomal loci. Analysis of the TgM revealed that RP-2 was essential to basal promoter activity in the kidney, while renin mRNA levels did not significantly change in any tissues tested in the CNRE mutant TgM. To evaluate the physiological significance of these mutations, we used the BAC Tg to rescue hypotensive Renin-null mutant mice. As predicted, no renin expression was observed in the kidneys of RP-2 mutant/Renin-null compound mice, whereas renin expression in CNRE mutant compound mice was indistinguishable from that in control mice. Consistent with this, RP-2 mutant animals were hypotensive, while CNRE mutants had normal blood pressure. Thus, transcriptional regulation of renin expression via RP-2 but not CNRE is critical for blood pressure regulation by this gene. IntroductionRenin is an aspartyl protease synthesized mainly in the juxtaglomerular (JG) cells of the kidney. It catalyzes cleavage of a unique substrate, angiotensinogen, a plasma protein synthesized predominantly in the liver; cleavage yields the decapeptide angiotensin I (AI). AI is further processed by angiotensin-converting enzyme to produce the octapeptide angiotensin II (AII), which mediates vasoconstriction and aldosterone secretion through angiotensin receptors (ATs), leading to increased BP. Renin catalyzes the first, rate-limiting reaction of the renin-angiotensin system and thus plays a central role in regulating overall activity of the renin-angiotensin system. Our lab and others have shown by gene ablation in the mouse that renin is essential to BP homeostasis (1, 2).A number of physiological stimuli, such as renal sympathetic activity, sodium depletion, and low BP, induce renin transcription and secretion in order to maintain BP homeostasis. Several of these stimuli utilize cAMP as an intracellular signal (reviewed in ref.3). In JG cells, noradrenalin released from sympathetic nerve endings activates adenylate cyclase. Intracellular cAMP concentration in JG cells can also be modified directly or indirectly by low distal tubular salt load, increased NO and prostaglandins, and/or decreased adenosine release from the macula densa. Pharmacological blockade of AII synthesis or receptor function also increases

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Identification of cis-Regulatory Sequences in the Human Angiotensinogen Gene by Transgene Coplacement and Site-Specific Recombination

Cited by 13 publications

References 48 publications

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

Analysis and validation of traits associated with a single nucleotide polymorphism Gly364Ser in catestatin using humanized chromogranin A mouse models

A single nucleotide mutation in the mouse renin promoter disrupts blood pressure regulation

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