Abstract
Elk-1, a member of the ternary complex factor family of Ets domain proteins that bind serum response elements, is activated by phosphorylation in a cell-specific manner in response to growth factors and other agents. The purpose of the current study was to determine whether Elk-1 activation contributes to glucose-/depolarization-induced Ca2+-dependent induction of immediate early response genes in pancreatic islet β-cells. The results of experiments in insulinoma (MIN6) cells demonstrated that Elk-1-binding sites (Ets elements) in the Egr-1 gene promoter contribute to transcriptional activation of the gene. Treatment with either epidermal growth factor (EGF), a known inducer of β-cell hyperplasia, glucose, or KCl-induced depolarization resulted in Ser383 phosphorylation and transcriptional activation of Elk-1 (4 ± 0.3-, P = 0.003, 2.3 ± 0.19-, P = 0.002, and 2.2 ± 0.1- fold, P = 0.001 respectively). The depolarization response was inhibited by the Ca2+ channel blocker verapamil and by the MEK inhibitor PD98059 (53 ± 6 and 55 ± 0.5%, respectively). EGF-induced activation of Elk-1 was also inhibited by PD98059 (60 ± 5%). A dominant negative Ras produced partial inhibition (42%) of the depolarization-induced Elk-1 transcriptional activation. Transfection with a constitutively active Ca2+/calmodulin kinase IV plasmid also resulted in Elk-1 transcriptional activation. Experiments with p38, phosphatidylinositol 3-kinase, and protein kinase A inhibitors indicated that these pathways are not involved. We conclude that Elk-1 activation contributes to glucose-/depolarization-induced Ca2+-dependent induction of immediate early growth response genes in pancreatic islet β-cells. Furthermore, the results demonstrated a convergence of nutrient- and growth factor-mediated signaling pathways on Elk-1 activation through induction of Ras/mitogen-activated protein kinase ERK-1 and -2. The role of these pathways in the glucose-induced proliferation of islet β-cells can now be assessed.
Original language | English (US) |
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Pages (from-to) | E1286-E1299 |
Journal | American Journal of Physiology - Endocrinology and Metabolism |
Volume | 281 |
Issue number | 6 44-6 |
DOIs | |
State | Published - 2001 |
Externally published | Yes |
Keywords
- Depolarization
- Egr-1
- Epidermal growth factor
- Growth factors
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology
- Physiology (medical)