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-IIdriven 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.

CREG1 Interacts with Sec8 to Promote Cardiomyogenic Differentiation and Cell-Cell Adhesion

“…Recently, CREG1 has also been found to reside in lysosomes where it is processed by cathepsin‐mediated cleavage in fibroblasts . Additionally, it has been colocalized with its putative receptor IGF2R on the plasma membrane in epithelial cells and smooth muscle . In the present study, CREG1 was observed mainly at cell‐cell junctions and an intracellular vesicular compartment in cardiomyocytes.…”

Increased Expression of Cellular Repressor of E1A-Stimulated Gene (CREG) in Gastric Cancer Patients: A Mechanism of Proliferation and Metastasis in Cancer

“…Therefore, after silencing the expression of CREG, other proliferation-related factors kept the cells growing and reproducing, but at a relatively lower rate of proliferation. Our data may conflict with some previous studies that claimed that higher expression of CREG leads to cellular growth suppression in many types of cells [14][15][16][17]. This may be true in some kinds of cells or in some animal models, but it was ascertained that in human GC cells, CREG contributes partly to the overgrown character of cancer cells.…”

The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation

“…We speculate that, by virtue of multivalent M6P clusters exposed on opposite sides of the dimer, CREG could induce dimerization of M6P͞IGF2R and thus promote uptake of the receptor from the cell surface. Recent studies have suggested that CREG may regulate M6P͞IGF2R levels in ileal epithelial cells (32). How the internalization of the CREG-M6P͞ IGF2R complex affects cell growth remains unclear.…”