title: The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells.
abstract: Glucocorticoids induce hypertrophy of the neonatal ileal mucosa but the molecular mechanisms behind this growth induction remain poorly understood. Ileal epithelial cells (IECs) are dependent upon IGF-II for proliferation both in vivo and in culture. The type-2 IGF receptor (IGFR-2) is a lysosomal transport protein that attenuates IGF-II-driven growth and is highly abundant in the ileum. The cellular repressor of E1A-stimulated genes (CREG) is a secreted phosphoglycoprotein that affects cell fate via ligand binding with IGFR-2, although the mechanism by which it does so is unknown. We hypothesized that glucocorticoids might facilitate IGF-mediated hypertrophy through CREG-mediated degradation of IGFR-2. To test this hypothesis, confluent rat IECs (IEC-18) were cultured for 72 h with or without dexamethasone (DEX) and harvested for Western blot, immunocytochemistry, gene array and CREG immunoneutralization experiments. IGFR-2 and CREG immunohistochemistry were also performed in archived ileal specimens from control and DEX-exposed newborn mice and extremely premature infants to investigate in vivo and clinical relevance. DEX exposure was found to diminish IGFR-2 immunolocalization in cultured rat IECs, newborn mouse ileal mucosa and human neonatal ileal mucosa. Gene array data indicated that IGFR-2 expression was unchanged with DEX treatment, suggesting a mechanism of protein degradation. CREG immunolocalization and abundance was found to be increased by DEX and immunoneutralization of CREG resulted in the abolition of IGFR-2 degradation. We have concluded that CREG is a secreted mediator by which DEX induces degradation of IGFR-2 and speculate that this is a fundamental mechanism of mucosal growth induction.
authors.affiliation: Department of Pediatrics, Division of Neonatology, University of Virginia Health Sciences, PO Box 800386, Charlottesville, Virginia 22908, USA. pvg4n@virginia.edu
authors.forename: P V
authors.initials: PV
authors.lastname: Gordon
authors.forename: J B
authors.initials: JB
authors.lastname: Paxton
authors.forename: N S
authors.initials: NS
authors.lastname: Fox
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D003907:Dexamethasone / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: C114068:CREG1 protein, human; D005938:Glucocorticoids; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D012097:Repressor Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D003907:Dexamethasone