Tissue specific expression of the human alpha-1-antitrypsin gene in transgenic mice

Sifers, Richard N.; Carlson, Joyce; Clift, Shirley M.; DeMayo, Francesco J.; Bullock, D. W.; Woo, Savio L. C.

doi:10.1093/nar/15.4.1459

Cited by 111 publications

(59 citation statements)

References 46 publications

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“…Although sexual dimorphism of prorenin levels has been detected in some strains of rats (32), the extent of sexual dimorphism in transgene expression in our study was unexpected because endogenous ␣ 1-antitrypsin expression is only severalfold higher in male rats than in females (33). Furthermore, RNase analysis showed that transgene mRNA level in Prorenin, PRA (plasma renin activity), and angiotensinogen measured in ng of angiotensin I/ml/h, * P Ͻ 0.001 vs. nontransgenic rats.…”

Section: Discussionmentioning

confidence: 54%

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Véniant¹,

Ménard²,

Bruneval³

et al. 1996

J. Clin. Invest.

156

123

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We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two transgenic rat lines were generated in which rat prorenin expression was directed to the liver by a human ␣ 1-antitrypsin promoter. Liver-specific expression was confirmed by RNase protection assay. Plasma prorenin concentrations in transgenic rats were increased 400-fold in the males of both lines but were increased only two-to threefold in the females. Thus, transgene expression exhibited sexual dimorphism. Blood pressures were not significantly higher in transgenic rats than in nontransgenic controls. The ratio of heart weight to body weight was greater in male transgenic rats than in the nontransgenic controls.

show abstract

Section: Discussionmentioning

confidence: 54%

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Véniant¹,

Ménard²,

Bruneval³

et al. 1996

J. Clin. Invest.

156

123

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“…Transgenic PiZ mice express human AAT-Z from its native promoter elements (12). Tissue distribution of transgene expression recapitulates that in humans (13).…”

Section: Resultsmentioning

confidence: 67%

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

Ding¹,

Yannam²,

Roy‐Chowdhury³

et al. 2011

J. Clin. Invest.

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α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z-expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%-98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z-expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.

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“…Although α1-antitrypsin variant PI Z misfolds following biosynthesis (Elliott et al, 1996) in response to a E342K substitution (Sifers et al, 1987), it fails to induce the UPR in any of the cell lines in which it has been expressed (Hidvegi et al, 2005;Lawless et al, 2004), including HEK293 (Cabral et al, 2002). Because variant PI Z is subject to proteasomal degradation in transfected HEK293 cells (Cabral et al, 2002;Wu et al, 2003) in the next set of experiments it served as a reporter protein to measure changes in the efficiency of ERAD under basal conditions and in response to the experimental overexpression, or knockdown, of ERManI or EDEM1.…”

Section: Knockdown Of Ermani But Not Edem1 Diminishes Basal Eradmentioning

confidence: 99%

The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I

Termine

Moremen

Sifers

2009

Journal of Cell Science

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a complex that suppresses the proteolytic downregulation of ER mannosidase I (ERManI). The results of site-directed mutagenesis indicate that this capacity does not require that EDEM1 possess inherent mannosidase activity. A model is proposed in which ERManI, by functioning as a downstream effector target of EDEM1, represents a checkpoint activation paradigm by which the mammalian UPR coordinates the boosting of ERAD.

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Tissue specific expression of the human alpha-1-antitrypsin gene in transgenic mice

Cited by 111 publications

References 46 publications

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver.

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I

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