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."
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.
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.
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.
This article was published in the following journal.
Name: BMC molecular biology
- 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
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).
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.
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.
BACKGROUND: Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in sev...
After a meal, insulin suppresses lipolysis through activation of its downstream kinase, Akt, resulting in inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin...
The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is...
Signal transducer and activator of transcription 3 (STAT3) is a key regulator of cytokine signaling pathways that regulates gene expression. In pancreatic cancer, constitutive activation of STAT3 cont...
Insulin-like growth factor 1 (IGF-1) inhibits 5-fluorouracil (5-Fu)-induced apoptosis in esophageal carcinoma cells; however, the mechanisms for IGF-1-induced 5-Fu chemoresistance remain unknown. In t...
The purpose of the study is to determine whether E1 and G1 are safe and effective in the treatment of type 1 diabetes. Type 1 diabetes is an autoimmune disease, in which the immune system...
The purpose of this study is to determine: 1. whether there is a difference between insulin aspart and insulin lispro in continuous insulin pump therapy 2. whether duratio...
The purpose of this clinical trial is to evaluate the ability of urinary Survivin mRNA measurement to estimate the risk of bladder cancer at the time of cystoscopy in subjects with no prio...
The primary aim of this study is to determine if mutations of BRCA1 and BRCA2 result in different precancerous pathways to pancreatic ductal adenocarcinoma (PDAC), as suggested in our vali...
The pancreas is an organ that plays major roles in the digestion of food. A part of the pancreas called islet beta-cells produces insulin, which regulates the amount of glucose (a sugar) p...