TY - JOUR
T1 - Insulin mediates glucose-stimulated phosphorylation of PHAS-I by pancreatic beta cells. An insulin-receptor mechanism for autoregulation of protein synthesis by translation
AU - Xu, Guang
AU - Marshall, Connie A.
AU - Lin, Tai An
AU - Kwon, Guim
AU - Munivenkatappa, Raghava B.
AU - Hill, Jeanette R.
AU - Lawrence, John C.
AU - McDaniel, Michael L.
PY - 1998/2/20
Y1 - 1998/2/20
N2 - Although glucose regulates the biosynthesis of a variety of beta cell proteins at the level of translation, the mechanism responsible for this effect is unknown. We demonstrate that incubation of pancreatic islets with elevated glucose levels results in rapid and concentration-dependent phosphorylation of PHAS-I, an inhibitor of mRNA cap-binding protein, eukaryotic initiation factor (eIF)-4E. Our initial approach was to determine if this effect is mediated by the metabolism of glucose and activation of islet cell protein kinases, or whether insulin secreted from the beta cell stimulates phosphorylation of PHAS-I via an insulin-receptor mechanism as described for iusulin-sensitive cells. In support of the latter mechanism, inhibitors of islet cell protein kinasea A and C exert no effect on glucose- stimulated phosphorylation of PHAS-I, whereas the phosphatidylinositol 3- kinase inhibitor, wortmannin, the immunosuppressant, rapamycin, and theophyllinne, a phosphodiesterase inhibitor, promote marked dephosphorylation of PHAS-I. In addition, exogenous insulin and endogenous insulin secreted by the beta cell line, βTC6-F7, increase phosphorylation of PHAS-I, suggesting that beta cells of the islet, in part, mediate this effect. Studies with beta cell lines and islets indicate that amino acids are required for glucose or exogenous insulin to stimulate the phosphorylation of PHAS-I, and amino acids alone dose-dependently stimulate the phosphorylation of PHAS-I, which is further enhanced by insulin. Furthermore, rapamycin inhibits by ~62% the increase in total protein synthesis stimulated by high glucose concentrations. These results indicate that glucose stimulates PHAS- I phosphorylation via insulin interacting with its own receptor on the beta cell which may serve as an important mechanmism for autoregulation of protein synthesis by translation.
AB - Although glucose regulates the biosynthesis of a variety of beta cell proteins at the level of translation, the mechanism responsible for this effect is unknown. We demonstrate that incubation of pancreatic islets with elevated glucose levels results in rapid and concentration-dependent phosphorylation of PHAS-I, an inhibitor of mRNA cap-binding protein, eukaryotic initiation factor (eIF)-4E. Our initial approach was to determine if this effect is mediated by the metabolism of glucose and activation of islet cell protein kinases, or whether insulin secreted from the beta cell stimulates phosphorylation of PHAS-I via an insulin-receptor mechanism as described for iusulin-sensitive cells. In support of the latter mechanism, inhibitors of islet cell protein kinasea A and C exert no effect on glucose- stimulated phosphorylation of PHAS-I, whereas the phosphatidylinositol 3- kinase inhibitor, wortmannin, the immunosuppressant, rapamycin, and theophyllinne, a phosphodiesterase inhibitor, promote marked dephosphorylation of PHAS-I. In addition, exogenous insulin and endogenous insulin secreted by the beta cell line, βTC6-F7, increase phosphorylation of PHAS-I, suggesting that beta cells of the islet, in part, mediate this effect. Studies with beta cell lines and islets indicate that amino acids are required for glucose or exogenous insulin to stimulate the phosphorylation of PHAS-I, and amino acids alone dose-dependently stimulate the phosphorylation of PHAS-I, which is further enhanced by insulin. Furthermore, rapamycin inhibits by ~62% the increase in total protein synthesis stimulated by high glucose concentrations. These results indicate that glucose stimulates PHAS- I phosphorylation via insulin interacting with its own receptor on the beta cell which may serve as an important mechanmism for autoregulation of protein synthesis by translation.
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U2 - 10.1074/jbc.273.8.4485
DO - 10.1074/jbc.273.8.4485
M3 - Article
C2 - 9468502
AN - SCOPUS:0032548831
SN - 0021-9258
VL - 273
SP - 4485
EP - 4491
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -