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- Author: G S G Spencer x
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Search for other papers by G S G Spencer in
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Search for other papers by J J Bass in
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ABSTRACT
Interactions between the IGF-binding proteins (IGFBPs) and glycosaminoglycans (GAGs) such as heparin may be involved in the regulatory control of IGF exerted by the IGFBPs at the level of the extracellular matrix and capillary endothelium, although the precise mechanisms of this remain uncertain. We have searched primary sequences of human, rat and bovine IGFBPs-1 to -6 for putative GAG-binding consensus sequences (XBBXBX and XBBBXXBX, where B represents any basic amino acid and X is undefined). At least one such sequence was identified in each IGFBP examined except human and rat IGFBP-4 and rat IGFBP-6, with IGFBP-5 containing three GAG-binding consensus sequences. Additionally, the bovine IGF type II receptor was found to contain two such sequences in the intracellular region. Affinity of the IGFBP preparations for heparin was examined experimentally by affinity chromatography using pooled fractions of fetal and adult ovine plasma obtained by size exclusion chromatography. Pooled fractions of 150 kDa (containing IGFBP-3 alone by IGF ligand blot analysis) and 40–50 kDa (containing IGFBPs-3 and -2, together with proteins of 29, 24 and 25–28 kDa which may include IGFBP-4 and IGFBPs-1, -5 and -6) were found to bind strongly to the matrix necessitating high salt concentrations for their elution; however, in contrast, a >200 kDa fraction containing the soluble form of the type II receptor failed to bind. Recombinant human non-glycosylated IGFBP-3 also bound strongly to the affinity adsorbent. No evidence of dissociation of bound IGF from binding protein complexes by association with the matrix was obtained from this experiment. This study provides a molecular basis for the interaction of IGFBPs with matrix GAGs, although precise mechanisms by which this may influence IGF bioactivity at the cellular level remain to be established.
Search for other papers by T E Spencer in
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Search for other papers by F W Bazer in
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ABSTRACT
This study determined the effects of intrauterine injections of recombinant ovine interferon-τ (roIFN-τ; 2 × 107 antiviral units/day) or control proteins (6 mg/day) from day 11 to day 14 post-oestrus (oestrus=day 0) on endometrial expression of receptors for oestrogen, progesterone and oxytocin in cyclic ewes. Plasma concentrations of progesterone were greater on day 15 in ewes receiving roIFN-τ compared with control proteins (P<0·02, treatment × day). Ewes injected with roIFN-τ had lower endometrial levels of oestrogen receptor mRNA (P<0·10) and protein (P<0·01) on day 15 compared with ewes receiving control proteins. In situ hybridization analysis indicated that oestrogen receptor mRNA was more abundant in the luminal and glandular epithelium of control ewes compared with roIFN-τ-treated ewes. Immunoreactive oestrogen receptor was also present in the luminal and glandular epithelium of control, but not roIFN-τ-treated ewes. Endometrial levels of progesterone receptor mRNA and protein were not different (P>0·10) between control and roIFN-τ-treated ewes. In situ hybridization analyses indicated that progesterone receptor mRNA abundance was low in endometrial epithelium and stroma of both control and roIFN-τ-injected ewes. Immunoreactive progesterone receptors were present in the endometrial stroma and epithelium of control ewes, but confined to the stroma of roIFN-τ-treated ewes. Oxytocin receptor density was lower (P<0·10) in the endometrium of ewes injected with roIFN-τ than control proteins; however, oxytocin receptor affinity was not affected (P>0·10) by treatment. Concentrations of 13,14-dihydro-15-keto-prostaglandin F2α (PGFM) were not increased by exogenous oxytocin administration in control and roIFN-τ-treated ewes on days 10 or 12 post-oestrus. However, on day 14, control ewes responded to oxytocin with increased plasma concentrations of PGFM, whereas ewes receiving roIFN-τ remained unresponsive to oxytocin. These results indicate that the antiluteolytic effects of IFN-τ are to prevent increases in endometrial oestrogen receptor mRNA and protein and oxytocin receptor density which abrogates uterine release of prostaglandin F2α during maternal recognition of pregnancy. IFN-τ may inhibit the synthesis of oestrogen receptor mRNA by a transcriptional or post-transcriptional regulatory mechanism to suppress oxytocin receptor formation during early pregnancy in ewes.
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Search for other papers by S A Spencer in
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Search for other papers by F J de Sauvage in
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ABSTRACT
Leptin, the product of the ob gene, is a hormone secreted by fat cells which is primarily involved in the regulation of body weight. We have generated a leptin immunoadhesin (leptin-IgG) which was more potent than leptin alone at reducing body weight and food intake when injected into ob/ob mice. This molecule was used to identify high affinity binding sites on human embryonic 293 kidney cells and subsequently to isolate a cDNA encoding the leptin receptor from this cell line by expression cloning. This receptor corresponds to the short form of the recently isolated leptin receptor. Analysis of the expression pattern of the two forms of receptor by Northern blot, in situ hybridization and quantitative PCR showed that the receptor is expressed in most tissues but that the long form is prevalent in the hypothalamus.
