Abstract
BackgroundPostnatal expansion of the pancreatic β-cell mass is required to maintain glucose homeostasis immediately after birth. This β-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of β-cells. Survivin, an oncofetal protein with both pro-proliferative and anti-apoptotic properties, is a known transcriptional target of both IGF-1 and EGF in cancer cells. Here, we analyzed the effects of the β-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic β-cell model cell lines, MIN6 and INS-1 and in primary mouse islets.ResultsIn pancreatic β-cells, treatment with glucose, insulin, or EGF increased survivin protein levels at early time points. By contrast, no significant effects on survivin were observed following IGF-1 treatment. EGF-stimulated increases in survivin protein were abrogated in the presence of downstream inhibitors of the Raf-1/MEK/ERK pathway. EGF had no significant effect on survivin transcription however it prolonged the half-life of the survivin protein and stabilized survivin protein levels by inhibiting surviving ubiquitination.ConclusionsThis study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic β-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating β-cell expansion after birth.
Highlights
Postnatal expansion of the pancreatic b-cell mass is required to maintain glucose homeostasis immediately after birth
epidermal growth factor (EGF) regulates survivin protein expression in pancreatic bcells To begin to understand the mitogenic responsiveness of survivin in pancreatic b-cells we made use of the immortalized mouse and rat b-cell lines, MIN6 and INS-1
MIN6 cells were cultured under proliferating conditions serum-and glucose-deprived for 2 to 4 hours, prior to treatment for 30 minutes with glucose or insulin
Summary
Postnatal expansion of the pancreatic b-cell mass is required to maintain glucose homeostasis immediately after birth This b-cell expansion is regulated by multiple growth factors, including glucose, insulin, insulin-like growth factor (IGF-1) and epidermal growth factor (EGF). These mitogens signal through several downstream pathways (AKT, ERK, STAT3, and JNK) to regulate the survival and proliferation of b-cells. Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, consisting of 4 transmembrane tyrosine kinase receptors: EGFR (ErbB1, HER1), ErB2 (neu/HER2), ErbB3 (HER3) and ErbB4 (HER4) [7,8] All such proteins contain an extracellular domain responsible for ligand binding, a single membrane-spanning domain, and a cytoplasmic tyrosine kinase domain with multiple auto-phosphorylation sites. EGF is a potent growth factor and one of the 11 ligands of this receptor that signals via multiple downstream pathways including: PI3K/AKT, ERK1/2, JNK, JAK/STAT3, and others, dependent on which of the 5 tyrosine residues is phosphorylated [7]
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