Cloning and characterization of the rat gene for the acid-labile subunit of the insulin-like growth factor binding protein complex

Delhanty, Patric J. D.; Baxter, Robert C.

doi:10.1677/jme.0.0190267

Cited by 16 publications

(18 citation statements)

References 47 publications

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“…We previously showed that these effects of GH are transcriptional and mediated by STAT5 binding to a single GAS element in the proximal promoter of the mouse ALS gene (Ooi et al 1998). This GAS element is completely conserved in the promoter of the rat, sheep and human ALS gene (Delhanty & Baxter 1997, Rhoads et al 2000, Suwanichkul et al 2000. A similar mechanism has recently been shown to explain the positive effects of GH on the transcription of the rat IGF-I gene (Woelfle et al 2003, Chia et al 2006.…”

Section: Discussionmentioning

confidence: 77%

Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation

Kim¹,

Rhoads²,

Segoale³

et al. 2006

Journal of Endocrinology

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During the transition from pregnancy to lactation, dairy cows experience a 70% reduction in plasma IGF-I. This reduction has been attributed to decreased hepatic IGF-I production. IGF-I circulates predominantly in multiprotein complexes consisting of one molecule each of IGF-I, IGF binding protein-3 and the acid labile subunit (ALS). Recent studies in the mouse have shown that absence of ALS results in accelerated turnover and severely depressed concentration of plasma IGF-I. These observations suggest that reduced plasma ALS could be a second factor contributing to the fall of plasma IGF-I in periparturient cows. This possibility has not been studied due to the lack of bovine ALS reagents. To address this, we isolated the bovine ALS cDNA and used its sequence to develop a ribonuclease protection assay (RPA) and a bovine ALS antiserum. Using the RPA, ALS mRNA abundance was approximately fivefold higher in liver than in lung, small intestine, adipose tissue, kidney and heart, but was absent in muscle and brain. The antiserum detected the highest ALS levels in plasma followed by ovarian follicular fluid, lymph and colostrum. A portion of colostrum and follicular fluid ALS appears to be synthesized locally as ALS mRNA was found in mammary epithelial cells and ovarian follicular cells. Finally, we measured plasma ALS in dairy cows during the periparturient period (days 35 and +56 relative to parturition on day 0). Plasma ALS dropped by 50% between late pregnancy and the first day of lactation and returned to prepartum levels by day +56. To determine whether this reflected a change in hepatic expression, ALS mRNA was measured in liver biopsies collected on days 35, +3 and +56. ALS mRNA expression was significantly lower on day +3 than on day 35, but recovered completely by day +56. Finally, we examined the ability of GH to increase plasma ALS abundance at selected times before and after parturition (weeks 5, 2, +1 and +5). GH increased plasma ALS at weeks 5, 2 and +5, but not at week +1. Identical effects of GH were seen when the response considered was plasma IGF-I. We conclude that the decline in plasma ALS after parturition is a consequence of hepatic GH resistance and contributes to the associated reduction of plasma IGF-I.

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Section: Discussionmentioning

confidence: 77%

Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation

Kim¹,

Rhoads²,

Segoale³

et al. 2006

Journal of Endocrinology

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“…Using fluorescence in situ hybridization, the gene was mapped to bands A2-A3 of the mouse chromosome 17 [23]. This organization is identical to that of the rat and sheep ALS genes ( [24]; unpublished results).…”

Section: Organization Of the Mouse Als Genementioning

confidence: 86%

“…Mature mouse ALS is 92% identical to rat ALS, and 77% identical to human ALS [25,26]. It is organized into 18-20 leucine-rich domains of 24 amino acids each, which are thought to confer to ALS its ability to associate with the IGFBP-3:IGF binary complexes [23,24,26]. Mature mouse ALS contains 13 cys-563 teine residues, which occur at identical positions in rat ALS, and at 12 of 13 positions in human ALS [25,26].…”

Section: Organization Of the Mouse Als Genementioning

confidence: 99%

Regulation and role of the acid-labile subunit of the 150-kilodalton insulin-like growth factor complex in the mouse

Boisclair

Hurst

Ueki

et al. 2000

Pediatric Nephrology

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After birth, the acid-labile subunit (ALS) associates in the circulation with insulin-like growth factor (IGF)-I or -II and with IGF binding protein-3 (IGFBP-3) to form a 150-kilodalton complex. This association leads to the retention of IGFs in the vascular system and promotes their endocrine actions. ALS is synthesized almost exclusively in liver, and both hepatic ALS mRNA and circulating levels are increased by growth hormone (GH). Three major areas of study were pursued to better understand the regulation of ALS synthesis and its role in the circulating IGF system. First, the mouse ALS gene was isolated and shown to be organized into two exons and a single intron on chromosome 17. Second, using transient transfection studies in the rat H4-II-E hepatoma cell line and primary rat hepatocytes, the region of the mouse promoter that is responsive to GH was mapped to a nine-base pair cis-element resembling a gamma-interferon-activated sequence. The activation of the mouse ALS gene by GH is mediated by the binding of STAT5 isoforms to this sequence. Finally, an ALS knockout model was created by inactivating the ALS gene in mouse embryonic stem cells. Mice that are homozygous for the mutation grow at a slower rate after birth. This growth depression is associated with large decreases in the plasma concentrations of both IGF-I and IGFBP-3, indicating the critical role of ALS in the regulation of circulating levels of these proteins. Studies of this model will lead to a better understanding of the circulating IGF system.

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“…ALS and IGF-I are expressed predominantly in the liver, and their expression is regulated at the level of transcription by GH (12,23,39). Additionally, we have found that insulin modulates hepatic expression of ALS (17, 18).…”

mentioning

confidence: 94%

Regulation of the acid-labile subunit in sustained endotoxemia

Kong

Firth

Baxter

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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The effect of sustained endotoxemia on expression of the acid-labile subunit (ALS) in relation to hepatic markers of altered GH and insulin sensitivity was examined. Juvenile rats were injected with endotoxin twice daily for 48 h, causing reduced food intake and attenuated growth. In pair-fed controls, food restriction caused marked suppression of ALS gene expression and circulating levels within 12 h, and endotoxemia augmented this effect. This acute effect of endotoxin corresponded temporally with transient induction of suppressor of cytokine signaling (SOCS)-3, cytokine-inducible SH2-containing protein (CIS), phosphoenolpyruvate carboxykinase (PEPCK), and insulin-like growth factor-binding protein (IGFBP)-1 and suppression of GH receptor (GHR). During the subsequent 36 h of sustained endotoxin treatment, expression of ALS recovered to, and then rose above, that of their pair-fed controls. This effect was paralleled by other ternary complex components. The inductive effect of sustained endotoxemia relative to pair-fed controls could not be explained by differences in expression of GHR, SOCS-3, or CIS but coincided with normalized PEPCK and IGFBP-1 levels, suggesting better hepatic insulin sensitivity in these animals. These data may indicate that, in sustained endotoxemia, ALS levels are regulated through modulation of hepatic insulin sensitivity. insulin sensitivity; insulin-like growth factor-binding protein-5; ternary complexes; liver THE ACID-LABILE SUBUNIT (ALS) of the 150-kDa insulinlike growth factor-binding protein (IGFBP) complex is an 85-kDa glycoprotein that is thought to regulate the bioavailability of IGFs in the serum, and possibly other tissue compartments, by sequestering them in a ternary complex with either IGFBP-3 or 6,13,22,48). Prolonged critical illness is characterized by severe wasting of lean body mass that has been attributed partly to suppression of the IGF axis (3,5,47,50). Concordantly, serum levels of ALS and other ternary complex components have been found to be decreased in critically ill patients (2,5,11,49).Circulating levels of ALS have been found to correlate strongly with IGFBP-3 and IGFBP-5 serum concentrations (7) and consequently would be expected to affect the bioavailability and metabolic activity of the IGFs in serum. ALS and IGF-I are expressed predominantly in the liver, and their expression is regulated at the level of transcription by GH (12,23,39). Additionally, we have found that insulin modulates hepatic expression of ALS (17, 18). Altered hepatic sensitivity to GH and insulin would be expected to modulate circulating levels of ALS and, consequently, other components of the ternary complexes.The effects of sustained endotoxemia on ALS expression have not yet been studied. Sustained endotoxemia in rats provides a model of inflammation-induced catabolism different from endotoxemic shock and very acute responses measured within hours of administration of a potentially lethal dose of lipopolysaccharide. We have used the model of sustained endotoxemia described by P...

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Cloning and characterization of the rat gene for the acid-labile subunit of the insulin-like growth factor binding protein complex

Cited by 16 publications

References 47 publications

Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation

Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation

Regulation and role of the acid-labile subunit of the 150-kilodalton insulin-like growth factor complex in the mouse

Regulation of the acid-labile subunit in sustained endotoxemia

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