EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic beta-cells.
Summary of "EGF regulates survivin stability through the Raf-1/ERK pathway in insulin-secreting pancreatic beta-cells."
ABSTRACT:
BACKGROUND:
Postnatal expansion of the pancreatic beta-cell mass is required to maintain glucose homeostasis immediately after birth. This beta-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 betacells. 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 beta-cell mitogens IGF-1 and EGF on survivin regulation in the established pancreatic beta-cell model cell lines, MIN6 and INS-1 and in primary mouse islets.
RESULTS:
In pancreatic beta-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 survivin ubiquitination.
CONCLUSIONS:
This study defines a novel mechanism of survivin regulation by EGF through the Raf-1/MEK/ERK pathway in pancreatic beta-cells, via prolongation of survivin protein half-life and inhibition of the ubiquitin-mediated proteasomal degradation pathway. This mechanism may be important for regulating beta-cell expansion after birth.
Affiliation
Journal Details
This article was published in the following journal.
Name: BMC molecular biology
ISSN: 1471-2199
Pages: 66
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20807437
- DOI: http://dx.doi.org/10.1186/1471-2199-11-66
Medical and Biotech [MESH] Definitions
Pancreatic Neoplasms
Tumors or cancer of the PANCREAS. Depending on the types of ISLET CELLS present in the tumors, various hormones can be secreted: GLUCAGON from PANCREATIC ALPHA CELLS; INSULIN from PANCREATIC BETA CELLS; and SOMATOSTATIN from the SOMATOSTATIN-SECRETING CELLS. Most are malignant except the insulin-producing tumors (INSULINOMA).
Insulin-secreting Cells
A type of pancreatic cell representing about 50-80% of the islet cells. Beta cells secrete INSULIN.
Carcinoma, Islet Cell
A primary malignant neoplasm of the pancreatic ISLET CELLS. Usually it involves the non-INSULIN-producing cell types, the PANCREATIC ALPHA CELLS and the pancreatic delta cells (SOMATOSTATIN-SECRETING CELLS) in GLUCAGONOMA and SOMATOSTATINOMA, respectively.
Pancreatic Polypeptide-secreting Cells
A group of islet cells (10-35%) which secrete PANCREATIC POLYPEPTIDE, a hormone that regulates APPETITE and FOOD INTAKE.
C-peptide
The middle segment of proinsulin that is between the N-terminal B-chain and the C-terminal A-chain. It is a pancreatic peptide of about 31 residues, depending on the species. Upon proteolytic cleavage of proinsulin, equimolar INSULIN and C-peptide are released. C-peptide immunoassay has been used to assess pancreatic beta cell function in diabetic patients with circulating insulin antibodies or exogenous insulin. Half-life of C-peptide is 30 min, almost 8 times that of insulin.
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