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  • American Diabetes Association  (2)
  • Goldfine, I D  (2)
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  • American Diabetes Association  (2)
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    Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit.
    American Diabetes Association ; 2000
    In:  Diabetes Vol. 49, No. 1 ( 2000-01-01), p. 13-19
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    In: Diabetes, American Diabetes Association, Vol. 49, No. 1 ( 2000-01-01), p. 13-19
    Abstract: Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling. PC-1 content is elevated in fibroblasts, muscle, and adipose tissue from insulin-resistant subjects, and its elevation correlates with in vivo insulin resistance. In vitro, when PC-1 is transfected and overexpressed in cultured cells, it inhibits IR tyrosine kinase activity. To determine the mechanism whereby PC-1 regulates the IR, we studied how PC-1 interacts with this protein. Overexpression of PC-1 in MCF-7 cells inhibited tyrosine kinase activity of the IR, but not of the IGF-I receptor. When the IR was immunocaptured by specific IR monoclonal antibodies, PC-1 was associated with this receptor. In contrast, after specific immunocapture, PC-1 was not associated with the IGF-I receptor. We next studied HTC cells that were overexpressing an IR alpha-subunit mutant. This IR mutant binds insulin but has a deletion in the tyrosine kinase regulatory domain located in amino acids 485-599. In contrast to normal IRs, PC-1 did not associate with this mutant and did not affect tyrosine kinase activity. To determine whether decreasing PC-1 expression would reverse the inhibition of tyrosine kinase activity, we treated MCF-7 cells overexpressing PC-1 with a monoclonal antibody to PC-1. This treatment decreased PC-1 levels; concomitantly, IR tyrosine kinase activity increased. In contrast, IGF-I receptor tyrosine kinase activity was not increased. These studies indicate, therefore, that PC-1 may inhibit the IR by interacting directly with a specific region in the IR alpha-subunit. These studies also raise the possibility that monoclonal antibodies to PC-1 could be a new treatment for insulin resistance.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.49.1.13
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2000
    detail.hit.zdb_id: 1501252-9
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  • 2
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    Online Resource
    Regulating Insulin-Receptor-Gene Expression by Differentiation and Hormones
    American Diabetes Association ; 1990
    In:  Diabetes Care Vol. 13, No. 3 ( 1990-03-01), p. 288-301
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 13, No. 3 ( 1990-03-01), p. 288-301
    Abstract: Insulin regulates cell function by first binding to the insulin receptor (IR) localized on the cell surface. With the cloning of IR cDNA and the IR-gene promoter, the regulation of the IR gene during differentiation and by various hormones can be studied. Muscle is a major target tissue for insulin action. BC3H1 cells, a mouse muscle cell line in culture, are a model cell type for studying insulin action. Differentiation in these cells results in a 5- to 10-fold increase in IR binding and a 5- to 10-fold increase in IR content. Studies of IR mRNA by Northern and slot-blot analyses reveal a 10-fold increase in IR mRNA after differentiation. These studies indicate that there is a selective increase in IR-gene expression during muscle differentiation. A similar increase in IRgene expression is observed for the IR during pancreatic acinar cell differentiation. Glucocorticoids increase IR content in several target tissues. Studies in cultured IM-9 lymphocytes indicate that glucocorticoids induce a 5-fold increase in IR mRNA levels. Studies of IR mRNA half-life indicate that glucocorticoids do not alter IR mRNA stability. When the transcription of the IR is measured by elongation assays, glucocorticoids directly stimulate IR transcription 5- to 10-fold. The effect is detectable within 30 min of glucocorticoid treatment and is maximal within 2 h. Therefore, these studies demonstrate that the IR gene is under the direct regulation of glucocorticoids. Insulin downregulates the IR in various target tissues. Prior studies indicate that this downregulation was partly because of accelerated IR degradation. Studying AR42J pancreatic acinar cells, we also found that insulin accelerates IR degradation. Moreover, in these cells, insulin decreases IR biosynthesis by ∼50%. Studies of IR mRNA indicate there is a concomitant decrease in IR mRNA levels after insulin treatment. Thus, insulin decreases IR-gene expression. The genomic structure of the IR promoter has been elucidated. Primer extension and nuclease S, analysis indicate that IR mRNA has multiple start sites. The promoter fragment was ligated to a promoterless “reporter” plasmid containing the bacterial gene chloramphenicol acetyltransferase (CAT). When this plasmid is transfected into cultured cells, CAT activity is detected, indicating promoter activity. Various portions of a genomic fragment were ligated to a promoter to study glucocorticoid regulation of the IR promoter. These studies indicate that IR-gene expression is regulated by differentiation and hormonal agents. Differentiation in muscle and acinar pancreas is associated with an increase in IRmRNA. When differentiated cells are studied, glucocorticoids upregulate IR-gene expression, whereas insulin downregulates this function.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.13.3.288
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1990
    detail.hit.zdb_id: 1490520-6
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