EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic β-cells

In 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.This 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.Production and maintenance of the pancreatic β-cell mass is a highly regulated process driven by four major mechanisms that include- β-cell replication, β-cell neogenesis, β-cell hypertrophy and β-cell apoptosis [1,2]. In the rodent, an exponential expansion of the pancreatic β-cell mass begins during the final phase of gestation and lasts through the third week after birth. Correspondingly, in humans, β-cell expansion occurs during the last trimester of pregnancy and continues through the first few months of life [1,2]. An increase in β-cell mass is required for insulin secretion in the maintenance of metabolic homeostasis [3], both in the initial transition to a carbohydrate-based diet following weaning and throughout life thereafter [4]. The molecular mechanisms regulating β-cell growth are mostly unknown but are dependent on a variety of growth factors, including glucose, insulin, insulin-like growth factor (IGF-I), and epidermal growth factor (EGF) [5,6], that provide mitogenic signals to the β-cell in vivo.Epidermal growth factor receptor (EGFR) is a member of the ErbB receptor family, consisting of 4 transmembrane tyrosine