Phosphoisoforms of insulin-like growth factor binding protein-1 in appropriate-for-gestational-age and small-for-gestational-age fetuses

Iwashita, Mitsutoshi; Sakai, Kiyofumi; Kudo, Y.; Takeda, Yoshihiko

doi:10.1016/s1096-6374(98)80302-x

Cited by 29 publications

(18 citation statements)

References 25 publications

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“…Later it was shown that the increase in IGFBP-1 is restricted to the phosphorylated isoform, which strongly inhibits IGF action, whereas levels of the nonphosphorylated isoform of IGFBP-1 are similar in small and average for gestational age infants (Iwashita et al 1998). Circulating IGFBP-1 levels also rise in response to fetal hypoxia, and the Igfbp-1 gene has a consensus sequence for the hypoxiaresponse element that binds hypoxia-inducible factor (Tazuke et al 1998).…”

Section: Origin Of Circulating Igfbpsmentioning

confidence: 99%

Altered expression of IGFs and IGF-binding proteins during intrauterine growth restriction in guinea pigs

Carter¹,

Kingston²,

Han³

et al. 2005

Journal of Endocrinology

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The IGF system is one of the most important endocrine and paracrine growth factor systems that regulate fetal and placental growth. We hypothesized that intrauterine growth restriction (IUGR) in guinea pigs is mediated by the altered expression of IGFs and/or IGF binding protein (BP) mRNAs in tissues and is related to growth of specific tissues. IUGR was induced by unilateral uterine artery ligation on day 30 of gestation, and fetal plasma, amniotic fluid and tissue samples were collected at 55-57 days (term about 68 days) from paired IUGR and control fetuses (n=6). Western ligand blotting and immunoblotting were used to compare IGFBP levels in plasma and amniotic fluid. Total RNA was extracted from placenta and fetal tissues, and the relative abundance of IGF-II and IGFBP-1-6 mRNA was determined by Northern blotting, using species-specific probes where available. IUGR fetuses had decreased (P<0·01, by Student's t-test) placental weight and body weight with an increase in the brain:liver weight ratio. The principal IGFBPs in fetal plasma migrated at 40-35, 30 and 25 kDa and were identified as IGFBP-3, -2 and -4 respectively. IUGR was associated with elevated plasma IGFBP-2 and IGFBP-4 and reduced IGFBP-3 levels. IGFBPs were detected at low levels in amniotic fluid of control fetuses but at higher levels in IUGR fetuses. In IUGR placentae, there was a small increase in IGFBP-4 mRNA (P<0·05). IGFBP-2 mRNA increased (P<0·001) in liver of IUGR fetuses. IGF-II and IGFBP mRNA expression did not change in fetal muscle. The results are consistent with reduced IGF action, directly or through inhibition by IGFBPs, particularly by circulating and tissue IGFBP-2, as a potential causal factor in decreased growth of the placenta and certain fetal tissues.

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Section: Origin Of Circulating Igfbpsmentioning

confidence: 99%

Altered expression of IGFs and IGF-binding proteins during intrauterine growth restriction in guinea pigs

Carter¹,

Kingston²,

Han³

et al. 2005

Journal of Endocrinology

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“…Jyung et al (11) also demonstrated that nonphosphorylated IGFBP-1 potentiates the ability of IGF-1 to stimulate wound healing. Iwashita et al (16) demonstrated that the proportion of nonphosphorylated IGFBP-1 in serum from appropriate-for-gestational-age fetuses was higher than that in serum from small-for-gestational-age fetuses at term, suggesting that the proportion of human IGFBP-1 phosphoisoforms is an important regulator of fetal growth. In contrast, Cox et al (12) reported that exogenous administration of recombinant human IGFBP-1 (nonphosphorylated IGFBP-1) inhibited the growth-promoting effects of IGF-1 on hypophysectomized rats.…”

Section: Phosphorylation Of Igfbp-1 and Glucose Metabolismmentioning

confidence: 99%

Physiological Differences in Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) Phosphorylation in IGFBP-1 Transgenic Mice

et al. 2001

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Insulin-like growth factor binding protein (IGFBP)-1 has been shown to alter cellular responses to insulinlike growth factor 1 (IGF-1). Human IGFBP-1 undergoes serine phosphorylation, and this enhances both its affinity for IGF-1 by six-to eightfold and its capacity to inhibit IGF-1 actions. To investigate the physiological role of IGFBP-1 in vivo, transgenic mice have been generated using either the human IGFBP-1 or rat IGFBP-1 transgene. Both lines of mice expressed high concentrations of IGFBP-1 in serum and tissues; however, human IGFBP-1 transgenic mice did not show glucose intolerance and exhibited no significant intrauterine growth retardation, whereas rat IGFBP-1 transgenic mice showed fasting hyperglycemia and intrauterine growth restriction. The aim of this study was to investigate the physiological differences in the phosphorylation state of human IGFBP-1 and rat IGFBP-1 in these transgenic mice. The phosphorylation status of IGFBP-1 in transgenic mouse serum was analyzed by nondenaturing PAGE. Almost all of the IGFBP-1 in serum from the human IGFBP-1 transgenic mice was present as a nonphosphorylated form. Most of the rat IGFBP-1 in the serum of the mice expressing the rat IGFBP-1 was phosphorylated. Immunoprecipitation showed that mouse hepatoma (Hepa 1-6) cells (exposed to [ 32 P]H 3 PO 4 ) secrete 32 P-labeled IGFBP-1. When the human IGFBP-1 transgene was transfected into Hepa 1-6 cells, all of the IGFBP-1 was secreted in the nonphosphorylated form. However, when the rat IGFBP-1 transgene was transfected into these cells, phosphorylated forms of IGFBP-1 were secreted. To confirm this result, the mouse hepatoma cell protein kinase was partially purified. This kinase activity phosphorylated mouse and rat IGFBP-1 in vitro, but it did not phosphorylate human IGFBP-1. Scatchard analysis showed that the affinity of phosphorylated rat IGFBP-1 for IGF-1 was 3.9-fold higher than that of nonphosphorylated human IGFBP-1. We conclude that the mouse IGFBP-1 kinase activity cannot phosphorylate human IGFBP-1, whereas it can phosphorylate rat IGFBP-1. The phosphorylation state of human IGFBP-1 may account for part of the phenotypic differences noted in the two studies of transgenic mice, and it is an important determinant of the capacity of human IGFBP-1 to inhibit IGF-1 actions in vivo.

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“…UV serum contains phosphorylated as well as less-and non-phosphorylated isoforms of IGFBP-1; SGA fetuses were found to have increased levels of phosphorylated, but not non-phosphorylated, IGFBP-1 (Iwashita et al 1996). Future studies should examine the phosphorylation pattern of IGFBP-1 in the fetal circulation in relation to PO 2 , insulin and cortisol levels.…”

Section: Discussionmentioning

confidence: 94%

Insulin-like growth factor-binding protein-1 in umbilical artery and vein of term fetuses with signs suggestive of distress during labor

Verhaeghe

Billen²,

Giudice³

2001

Journal of Endocrinology

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Insulin-like growth factor-binding protein-1 (IGFBP-1) is believed to be an inhibitory factor for fetal growth. The regulation of IGFBP-1 secretion in the fetus is uncertain, although insulin and oxygen tension (PO 2 ) and saturation are thought to play a role. We studied IGFBP-1 levels in umbilical cord artery (UA) and vein (UV) of 98 singleton fetuses at term with clinical signs of distress during labor, i.e. meconium-stained liquor or/and an abnormal fetal heart rate tracing. Blood gas values and serum C-peptide and IGFBP-1 concentrations were measured in both UA and UV. Twenty-five fetuses had an UA pH<7·20. The concentrations of IGFBP-1 were similar in UA and UV and were highly correlated (r=0·98). IGFBP-1 levels were inversely correlated with birth weight, with increased concentrations in small-for-gestational age fetuses (c10th weight percentile). IGFBP-1 levels were negatively correlated with C-peptide concentrations, and remained so after correction for birth weight (r= 0·37 for both UA and UV; P<0·001); more specifically, IGFBP-1 levels were increased in the lowest C-peptide quartile (<0·23 nmol/l) compared with the other quartiles. In addition, IGFBP-1 levels were inversely correlated with PO 2 values (r= 0·39 in UA and r= 0·34 in UV; P<0·001); quartiles of UA and UV PO 2 showed a gradual increase in IGFBP-1 concentrations with lower PO 2 values. A regression model with C-peptide and PO 2 values as independent variables predicted IGFBP-1 concentrations (R 2 of model was 0·25 and 0·22 for UA and UV respectively; P<0·001). Other blood gas values (pH, PCO 2 , HCO 3 and base deficit) did not correlate with IGFBP-1 levels. The data of this study indicate that serum IGFBP-1 levels in term fetuses are determined by both insulin and PO 2 levels, and suggest that acute hypoxemia stimulates IGFBP-1 secretion in the fetus.

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Phosphoisoforms of insulin-like growth factor binding protein-1 in appropriate-for-gestational-age and small-for-gestational-age fetuses

Cited by 29 publications

References 25 publications

Altered expression of IGFs and IGF-binding proteins during intrauterine growth restriction in guinea pigs

Altered expression of IGFs and IGF-binding proteins during intrauterine growth restriction in guinea pigs

Physiological Differences in Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1) Phosphorylation in IGFBP-1 Transgenic Mice

Insulin-like growth factor-binding protein-1 in umbilical artery and vein of term fetuses with signs suggestive of distress during labor

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