Tissue-Specific Regulation of Human α<sub>1</sub>-Antitrypsin Gene Expression in Transgenic Mice

Shen, Rong-Fong; Clift, Shirley M.; DeMayo, Janet L.; Sifers, Richard N.; Finegold, Milton J.; Woo, Savio L. C.

doi:10.1089/dna.1.1989.8.101

Cited by 28 publications

(22 citation statements)

References 42 publications

(35 reference statements)

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“…The nuclei were suspended in the same buffer also containing 1 mM EDTA. Nuclear proteins were extracted by the addition of 5 M KCl to a final concentration of 0.3 M. After centrifugation the final supernatant was adjusted to 0.1 M KCl by the addition of buffer A100 [20,21].…”

Section: Preparation Of Cell Extractsmentioning

confidence: 99%

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Rietveld

Holthuizen

Sussenbach

1997

Biochemical Journal

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Transcription of the human insulin-like growth factor II (IGF-II) gene is under the control of four promoters (P1-P4) that are differentially active during growth and development. Promoter 3 (P3) is the most active promoter during fetal development as well as in most adult tissues. P3 is also the most active promoter in tumour tissues and cell lines expressing IGF-II. Transient transfections of HeLa and Hep3B cells with truncated promoter constructs revealed that the region between -289 and -183 relative to the transcription start site supports basal promoter activity in both cell lines. Footprint experiments showed that the region between positions -192 and -172 (P3-4) is the only element bound by nuclear proteins. P3-4 is bound by five proteins, of which three proteins (proteins 3, 4 and 5) bind specifically and are expressed at the same levels in HeLa and Hep3B cells. Electrophoretic mobility shift assays and differential footprint experiments revealed the presence of two protein-binding regions within the P3-4 element. Proteins 4 and 5 bind box A (-193 to -188), whereas box B (-183 to -172) is bound by protein 3. From transcription experiments in vitro it can be concluded that Box A is essential for P3 activity. Box A is part of a region 11 dG residues long and is protected by proteins 4 and 5 that bind a contiguous set of six dG residues. DNA-binding of proteins 4 and 5 to box A requires the presence of Zn2+ ions. Thus structural and functional analysis reveals that the P3-4 element is a key regulatory element of P3 that contains two separate binding sites for proteins essential for the basal activity of IGF-II P3.

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Section: Preparation Of Cell Extractsmentioning

confidence: 99%

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Rietveld

Holthuizen

Sussenbach

1997

Biochemical Journal

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“…Figure 5A shows the location of restriction sites in the hAAT promoter. 24 BamH I sites are present at -46 and -1200 bp relative to the transcription initiation site; BamH I is unaffected by the methylation state of the DNA. The recognition site for both Hpa II DNA samples showed that the total signal in each lane is proportional to the amount of DNA present, making it impossible that 90% of the cells had lost expression because of deletion of the transgene.…”

Section: Analysis Of the Methylation State And The Copy Number Of Dnamentioning

confidence: 99%

Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream*1

KENNEDY¹

1995

Hepatology

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One hypothesis is that postnatal liver growth involves replication of mature hepatocytes, which have an unlimited proliferative potential. An alternative viewpoint is that only certain periportal cells can replicate extensively and that daughter cells stream slowly from the periportal to the pericentral region of the liver. The source of proliferating cells in both the normal and the regenerating liver is controversial. Some investigators favor the hypothesis that all parenchymal hepatocytes are capable of replication regardless of posiAbbreviations: BrdU, bromodeoxyuridine; fl-gal, beta-galactosidase; PCR, polymerase chain reaction; hAAT, human al antitrypsin; PBS, phosphatebuffered solution; TE, Tris-EDTA; FACS, fluorescence activated cell sorting; FDG, fluorescein-di-/%galactoside; FU, fluorescence units; EDTA, ethylene diaminetetraacetic acid; apo-VLDL-II, very low density apolioprotein II; LPS, lipopolysaccharide; uPA, urokinase plasminogen activator.From the Departments of 1Internal Medicine, 2Biochemistry and Molecular Biophysics, and 3Surgery,

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“…It is minimally expressed in the adult except during injury and repair, such as following PH in mice and hepatocellular carcinoma (HCC) in mice and humans (20). In the course of studies exploring the biological role of TWEAK, we prepared a transgenic mouse expressing the gene under control of the α1 antitrypsin (AAT) promoter, which is primarily expressed in the liver (22). The livers in these mice exhibited a striking periportal outgrowth of oval cells but otherwise appeared healthy.…”

Section: Introductionmentioning

confidence: 99%

TWEAK induces liver progenitor cell proliferation

Jakubowski

Ambrose²,

Parr³

et al. 2005

J. Clin. Invest.

368

357

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Progenitor ("oval") cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors.

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Tissue-Specific Regulation of Human α₁-Antitrypsin Gene Expression in Transgenic Mice

Cited by 28 publications

References 42 publications

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream*1

TWEAK induces liver progenitor cell proliferation

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Tissue-Specific Regulation of Human α1-Antitrypsin Gene Expression in Transgenic Mice

Cited by 28 publications

References 42 publications

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Identification of a key regulatory element for the basal activity of the human insulin-like growth factor II gene promoter P3

Experiments in transgenic mice show that hepatocytes are the source for postnatal liver growth and do not stream*1

TWEAK induces liver progenitor cell proliferation

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Tissue-Specific Regulation of Human α₁-Antitrypsin Gene Expression in Transgenic Mice