Open Access Highly Accessed Research article

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

Haijuan Wang1, Katarina Gambosova2, Zachary A Cooper1, Michael P Holloway1, Andrea Kassai1, Denisse Izquierdo1, Kelly Cleveland2, Charlotte M Boney2 and Rachel A Altura1*

Author Affiliations

1 Department of Pediatrics, Division of Pediatric Hematology-Oncology, Brown University, Providence, RI, 02903 USA

2 Department of Pediatrics, Division of Pediatric Endocrinology, Brown University, Providence, RI, 02903 USA

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BMC Molecular Biology 2010, 11:66  doi:10.1186/1471-2199-11-66

Published: 31 August 2010

Abstract

Background

Postnatal 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.

Results

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.

Conclusions

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.