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

Department of Pediatrics, Division of Pediatric Hematology-Oncology, Brown University, Providence, RI 02903, USA.
BMC Molecular Biology (Impact Factor: 2.19). 08/2010; 11(1):66. DOI: 10.1186/1471-2199-11-66
Source: PubMed


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.
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.

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    • "Recent studies reveal that the proteasomal degradation of survivin can also be affected by activation of various growth factor signaling pathways. For example, a study carried out by Wang et al25 showed that treatment with nutrients and growth factors, including glucose and epidermal growth factor (EGF), prompted an increased survivin protein expression in both mouse MIN6 and rat INS-1 pancreatic β-cells without significant increase in survivin mRNA levels or activation of survivin promoter. Moreover, the addition of EGF was shown to prevent polyubiquitination of survivin, thereby protecting survivin from degradation.25 "
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    ABSTRACT: Survivin is a member of the inhibitor-of-apoptosis proteins (IAPs) family; its overexpression has been widely demonstrated to occur in various types of cancer. Overexpression of survivin also correlates with tumor progression and induces anticancer drug resistance. Interestingly, recent studies reveal that survivin exhibits multiple pro-mitotic and anti-apoptotic functions; the differential functions of survivin seem to be caused by differential subcellular localization, phosphorylation, and acetylation of this molecule. In this review, the complex expression regulations and post-translational modifications of survivin are discussed. This review also discusses how recent discoveries improve our understanding of survivin biology and also create opportunities for developing differential-functioned survivin-targeted therapy. Databases such as PubMed, Scopus® (Elsevier, New York, NY, USA), and SciFinder® (CAS, Columbus, OH, USA) were used to search for literature in the preparation of this review.
    Full-text · Article · Oct 2013 · OncoTargets and Therapy
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    • "EGF-mediated induction of survivin requires the activity of Raf-1 and MEK/ERK, but EGF has no significant effect on survivin transcription. It prolongs the half-life of the survivin protein and stabilizes it by inhibiting survivin ubiquitination [68]. Many antibodies and small molecular-weight compounds aimed at members of the EGF receptor family and its downstream effectors are registered drugs or in clinical development [69]. "
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    ABSTRACT: Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand-survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.
    Full-text · Article · Aug 2013 · BioDrugs
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    • "Elevated fasting blood glucose is a hallmark characteristic of individuals with frank T2D.3,25,26 Short-term low levels of glucose induce Survivin expression after serum starvation.27 Yet, whereas hyperglycemia is presumed to ultimately provoke β-cell apoptosis and impair proliferation,28 how hyperglycemia/glucotoxic stress alters Survivin protein expression has never been addressed. "
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    ABSTRACT: Functional β-cell mass deficiency in diabetes results from imbalanced β-cell death and replication, and decreased PAK1 protein levels in human islets from donors with type 2 diabetes implicates a possible role for PAK1 in maintaining β-cell mass. Here, we aim to address the linkage between PAK1 and Survivin, a protein essential for β-cell replication. PAK1 knockout (KO) mouse islets exhibited decreased expression of Survivin protein. MIN6 β-cells with siRNA-mediated suppression of PAK1 also had decreased Survivin protein and exhibited an increased level of ubiquitinated-Survivin. However, no significant changes in Survivin mRNA were found in islets from PAK1 KO mice and PAK1-depleted MIN6 β-cells. The decreased Survivin level in MIN6 cells subjected to hyperglycemic stress was prevented by expression of exogenous PAK1. Moreover, overexpressing Survivin restored proliferation of β-cells that was impaired by the loss of PAK1. These data implicate a role for PAK1 in regulating Survivin protein stability in the β-cell and suggest PAK1 as a potential molecular target for the restoration of β-cell mass.
    Full-text · Article · Apr 2013 · Islets
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