Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution.

Hagiya, Michio; Francavilla, A.; Polimeno, Lorenzo; Ihara, Izumi; Sakai, Harumi; Seki, Tatsuya; Shimonishi, Manabu; Porter, Kenneth Wiggins; Starzl, Thomas E.

doi:10.1073/pnas.91.17.8142

Cited by 157 publications

(127 citation statements)

References 32 publications

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“…Although HSS had been recently sequenced [32], but the deduced molecule did not contain the structure necessary for growth signal transduction, nor homology to the other well-known hepatotrophic factor such as insulin, insulin-like growth factor (IGF), TGF-α;, even hepatocyte growth factor (HGF). Surprisingly, it did share 50% amino acid homology to the product of a nuclear gene, ERV1 in yeast [33], which played a critical role in the cell growth regulation [34].…”

Section: Discusionmentioning

confidence: 99%

Growth induction of hepatic stimulator substance in he-patocytes through its regulation on EGF receptors

Liu

Lei

et al. 1999

Cell Res

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The cytosolic liver-specific growth factor-hepatic stimulator substance (HSS) has been shown to be able to amplify the rat hepatocyte proliferation responded to EGF. In order to get more insight into the mechanism, the regulatory effect of HSS on EGF-receptor (EGF-R) and the receptor phosphorylation at molecular level was studied. HSS partially purified from weanling rat liver was given to cultured hepatocytes and its influence on EGF-R specific binding and internalization as well as mRNA expression were investigated. The results showed that preincubation of hepatocytes with HSS could lead to an increase in [ 125 I]-EGF binding to its receptors and inhibit EGFinduced receptor down-regulation. Furthermore, the over-expression of EGF-R mRNA stimulated by HSS was seen during 2-12 h after the incubation. Additionally, it was demonstrated with human hepatoma SMMC-7721 cells in Western blot that the EGF-R expression and the receptorautophosphorylation were increased with dose/time-dependency after HSS treatment . These results strongly suggest that the mechanism of HSS action on hepatocyte growth might be related to its modulation on EGF-R and receptor-mediated signaling transduction .

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Section: Discusionmentioning

confidence: 99%

Growth induction of hepatic stimulator substance in he-patocytes through its regulation on EGF receptors

Liu

Lei

et al. 1999

Cell Res

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“…Hepatic stimulator substance (HSS), a liver growth-promoting factor, was initially identified in the liver of weanling rats (LaBrecque and Pesch, 1975) and reported to stimulate remnant liver regeneration after partial hepatectomy (PH) (LaBrecque et al, 1987;Hagiya et al, 1995). HSS has also been referred to as augmenter of liver regeneration (ALR) or hepatopoietin, as it is able to enhance the growth of hepatocytes or hepatoma cells when combined with other hepatotrophic mitogens, such as epidermal growth factor (EGF) and transforming growth factor (TGF)-a, regardless of the animal species.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

Jiang

2013

Human Gene Therapy

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Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia-reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia-reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia-reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice.

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“…8,[25][26][27] Eventually, the peptide purified from HSS was renamed augmenter of liver regeneration (ALR) 8 and cloned. 28,29 The cDNA for rat ALR encodes a protein containing 198 amino acid residues and has a molecular weight of about 22 kd. 29,30 Cloned mouse and human ALR genes 30 that have highly conserved nucleotide and predicted amino acid sequences have been mapped to allele-rich regions of mouse chromosome 17 and human chromosome 16.…”

mentioning

confidence: 99%

“…28,29 The cDNA for rat ALR encodes a protein containing 198 amino acid residues and has a molecular weight of about 22 kd. 29,30 Cloned mouse and human ALR genes 30 that have highly conserved nucleotide and predicted amino acid sequences have been mapped to allele-rich regions of mouse chromosome 17 and human chromosome 16. 30 Meanwhile, the six additional molecules annotated in Table 1 [6][7][8][9]12,14,15, also had been shown to have primingdependent hepatotrophic qualities comparable with insulin and ALR.…”

mentioning

confidence: 99%

A fresh look at augmenter of liver regeneration in rats

et al. 1999

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Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reversetranscriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a timedependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration. (HEPATOLOGY 1999;29:1435-1445.)The control of hepatic growth and regeneration has interested experimentalists for much of the 20th century. 1 Soon after the classical description in 1931 by Higgins and Anderson 2 of liver regeneration in rats following 70% hepatectomy, a search began for growth factors within the liver itself. McJunkin and Breuhaus 3 observed that the modest mitotic response to a 30% to 40% hepatectomy in rats was enhanced with an intraperitoneal injection 2 days postoperatively of homogenized homologous rat liver. Two decades later, Teir and Ravanti 4 and Blomquist 5 noted that this ''augmentation'' effect was demonstrable only when the injected homogenates were prepared from regenerating liver fragments following hepatectomy or from weanling rat livers that have a naturally heightened mitotic index. Subsequently, LaBrecque and Pesch 6 reported the same prerequisite of a hyperplastic liver source for cytosol extracts containing a putative ''hepatic stimulatory substance'' (HSS).Importantly, however, a cocondition for demonstrating a mitosis-augmenting a...

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Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution.

Cited by 157 publications

References 32 publications

Growth induction of hepatic stimulator substance in he-patocytes through its regulation on EGF receptors

Growth induction of hepatic stimulator substance in he-patocytes through its regulation on EGF receptors

Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

A fresh look at augmenter of liver regeneration in rats

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