A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction
A member of Forkhead family transcription factor, FKHRL1, is one of the downstream molecules of phosphatidylinositol 3-kinase-Akt activation pathway in erythropoietin signal transduction
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DOI：
10.1182/blood.v96.3.941.015k14_941_949
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发表时间：
2000-08-01
期刊：
影响因子：
20.3
通讯作者：
Komatsu, N
中科院分区：
文献类型：
--
作者：
Kashii, Y;Uchida, M;Komatsu, N
磷脂酰肌醇3-激酶（PI3K）信号通路对许多细胞反应的调节是重要的。丝氨酸/苏氨酸激酶AM （protein kinase B， PKB）位于PI3K的下游，受生长因子激活。本研究发现，促红细胞生成素（EPO）在EPO依赖的人白血病细胞系ut7 /EPO中诱导AM的酪氨酸磷酸化具有时间和剂量依赖性，以组蛋白H2B和葡萄糖合酶激酶为底物进行的体外激酶试验表明，AM实际上被EPO激活，EPO诱导的AM磷酸化被PI3K特异性抑制剂LY294002完全阻断，浓度为10 μ mol/L，表明EPO对AM的激活依赖于PI3K活性。此外，在UT-7/EPO细胞上过表达构成活性形式的AM部分阻断了EPO从培养基中退出引起的细胞凋亡。这一发现提示PI3K-Akt激活通路在EPO的抗凋亡作用中起一定作用，在UT-7/EPO细胞中，EPO诱导转录因子Forkhead家族成员FKHRL1苏氨酸32和丝氨酸253位点的磷酸化，并呈剂量依赖性和时间依赖性。此外，结果表明，EPO激活AM激酶可直接磷酸化FKHRL1蛋白，并且FKHRL1的磷酸化与AW一样完全依赖于PI3K活性。结合FKHRL1在正常人红细胞祖细胞和红母细胞中表达的证据，结果表明FKHRL1作为PI3K- akt的下游靶分子之一，在红细胞生成中发挥重要作用。(C) 2000年由美国血液学会出版。
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is important for the regulation of a number of cellular responses. Serine/threonine kinase AM (protein kinase B; PKB) Is downstream of PI3K and activated by growth factors. This study found that erythropoietin (EPO) induced tyrosine phosphorylation of AM in a time- and dose-dependent manner in EPO-dependent human leukemia cell line UT-7/EPO, In vitro kinase assay using histone H2B and glucose synthase kinase as substrates demonstrated that AM was actually activated by EPO, EPO-induced phosphorylation of AM was completely blocked by a PI3K-specific inhibitor, LY294002, at 10 mu mol/L, indicating that activation of AM by EPO is dependent on PI3K activity. In addition, overexpression of the constitutively active form of AM on UT-7/EPO cells partially blocked apoptosis induced by withdrawal of EPO from the culture medium. This finding suggested that the PI3K-Akt activation pathway plays some role in the antiapoptotic effect of EPO, EPO induced phosphorylation of a member of the trancription factor Forkhead family, FKHRL1, at threonine 32 and serine 253 in a dose- and time-dependent manner in UT-7/EPO cells. Moreover, results showed that AM kinase activated by EPO directly phosphorylated FKHRL1 protein and that FKHRL1 phosphorylation was completely dependent on PI3K activity as Is the case for AW, In conjunction with the evidence that FKHRL1 is expressed in normal human erythroid progenitor cells and erythroblasts, the results suggest that FKHRL1 plays an important role in erythropoiesis as one of the downstream target molecules of PI3K-Akt. (C) 2000 by The American Society of Hematology.