Smith L K, Vlahos C J, Reddy K K, Falck J R, Garner C W
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock 79430, USA.
Mol Cell Endocrinol. 1995 Aug 30;113(1):73-81. doi: 10.1016/0303-7207(95)03622-e.
The insulin receptor substrate-1 (IRS-1) is expressed in 3T3-L1 adipocytes and is involved in at least some insulin responses, notably mitogenesis. Chronic exposure to insulin down regulates IRS-1 in these cells by stimulating its degradation (Rice, K.M., Turnbow, M.A. and Garner, C.W. (1993) Biochem. Biophys. Res. Commun. 190, 961-967). This insulin response was completely inhibited by wortmannin and LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), two inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase). Neither wortmannin nor LY294002 had any effect on the calcium-dependent degradation of IRS-1 in vitro nor did they inhibit the phosphorylation of IRS-1 in vitro. In addition, neomycin, a cationic aminoglycoside antibiotic that binds to phosphoinositides, inhibited the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes and, also, the C8-PIP3-stimulated degradation of IRS-1 in vitro. These results suggest that PI 3-kinase and its 3-phosphoinositide products mediate the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes.
胰岛素受体底物-1（IRS-1）在3T3-L1脂肪细胞中表达，并参与至少一些胰岛素反应，尤其是有丝分裂。长期暴露于胰岛素会通过刺激其降解来下调这些细胞中的IRS-1（赖斯，K.M.，特恩博，M.A.和加纳，C.W.（1993年）《生物化学与生物物理研究通讯》190，961-967）。这种胰岛素反应被渥曼青霉素和LY294002（2-（4-吗啉基）-8-苯基-4H-1-苯并吡喃-4-酮）完全抑制，这两种是磷脂酰肌醇3-激酶（PI 3-激酶）的抑制剂。渥曼青霉素和LY294002在体外对IRS-1的钙依赖性降解均无任何影响，在体外也不抑制IRS-1的磷酸化。此外，新霉素是一种与磷酸肌醇结合的阳离子氨基糖苷类抗生素，它抑制3T3-L1脂肪细胞中胰岛素诱导的IRS-1下调，并且在体外也抑制C8-PIP3刺激的IRS-1降解。这些结果表明PI 3-激酶及其3-磷酸肌醇产物介导3T3-L1脂肪细胞中胰岛素诱导的IRS-1下调。
