Differentiation-inducing factor-1-induced growth arrest of K562 leukemia cells involves the reduction of ERK1/2 activity
Differentiation-inducing factor-1-induced growth arrest of K562 leukemia cells involves the reduction of ERK1/2 activity
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DOI：
10.1016/j.ejphar.2003.11.041
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发表时间：
2004-02-06
影响因子：
5
通讯作者：
Kubohara, Y
中科院分区：
文献类型：
--
作者：
Akaishi, E;Narita, T;Kubohara, Y
分化诱导因子-1(DIF-1)是一种信号分子，可以诱导盘基网柄菌的细胞黏液霉菌柄细胞分化。此外，DIF-1是一种有效的抗白血病药物，可诱导K562细胞生长停滞。本研究从细胞周期蛋白、视网膜母细胞瘤蛋白(PRB)和丝裂原活化蛋白激酶(MAPK)家族等细胞周期调控因子的角度探讨了DIF-1在K562细胞中的作用机制。DIF-1下调细胞周期蛋白D/E和一种磷酸化形式的pRB(p-pRB)，从而诱导细胞周期G期停滞。DIF-1以双相方式失活细胞外信号调节激酶(ERK)，但不影响c-jun氨基末端激酶(JNK)或p38MAPK。MAPK(MAPK)抑制剂U0126可使细胞生长停滞，使ERK失活，并下调细胞周期蛋白D和E的表达。虽然DIF-1激活了磷脂酰肌醇3-激酶(PI-3K)/AKT通路，但Wortmannin和2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(PI-3K抑制剂)都不能阻断DIF-1诱导的生长停滞。提示ERK失活可能参与了DIF-1诱导的K562细胞生长停滞，而PI-3K活性不是DIF-1诱导K562细胞生长停滞所必需的。(C)2003爱思唯尔B.V.保留所有权利。
The differentiation-inducing factor-1 (DIF-1) is a signal molecule that induces stalk cell differentiation in the cellular slime mold Dictyostelium discoideum. In addition, DIF-1 is a potent antileukemic agent that induces growth arrest in K562 cells. In this study, we investigated the mechanism of action of DIF-1 in K562 cells in the light of cell-cycle regulators such as cyclins, retinoblastoma protein (pRb), and the mitogen-activated protein kinase (MAPK) family. DIF-1 down-regulated cyclins D/E and a phosphorylated form of pRb (p-pRb), and thereby induced G, arrest of the cell cycle. DIF-1 inactivated the extracellular signal-regulated kinase (ERK) in a biphasic manner but did not affect the c-Jun N-terminal kinase (JNK) or p38 MAPK. The MEK (MAPK kinase) inhibitor, U0126, which has been shown to induce growth arrest, inactivated ERK and down-regulated cyclins D and E. Although DIF-1 activated the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway, neither wortmannin nor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; PI-3K inhibitors) cancelled DIF-1-induced growth arrest. The present results suggest that ERK inactivation may be involved in DIF-1-induced growth arrest and that PI-3K activity is not required for DIF-1-induced growth arrest in K562 cells. (C) 2003 Elsevier B.V. All rights reserved.