A New alpha5beta1 integrin-dependent survival pathway through GSK3beta activation in leukemic cells.
A New alpha5beta1 integrin-dependent survival pathway through GSK3beta activation in leukemic cells.
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白血病细胞中通过 GSK3beta 激活建立的新的 α5β1 整合素依赖性生存途径。
DOI：
10.1371/journal.pone.0009807
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发表时间：
2010-03-23
期刊：
影响因子：
3.7
通讯作者：
Racaud-Sultan C
中科院分区：
文献类型：
--
作者：
De Toni-Costes F;Despeaux M;Bertrand J;Bourogaa E;Ysebaert L;Payrastre B;Racaud-Sultan C
整合素参与介导的细胞存活与细胞粘附介导的耐药有关。我们最近已经证明糖原合成酶激酶3β (GSK3β)的激活是支持白血病细胞粘附在纤维连接蛋白上的化疗耐药的新途径。我们在此发现，在血清饥饿条件下，纤维连接蛋白受体α5β1整合素，而不是α4β1，通过Ser-9去磷酸化诱导GSK3β在粘附的U937细胞中活化。gsk3 β依赖的存活途径出现在患者的黏附白血病细胞中，但不存在于HL-60和KG1细胞系中。在黏附过程中，活化的GSK3β存在于细胞质/质膜间室中，并与α5整合素、磷酸酶PP2A和支架蛋白RACK1共免疫沉淀。PP2A及其调控亚基B′调控GSK3β的Ser-9磷酸化。在粘附的白血病细胞中，α5β1整合素上调而α4β1不上调tnf α诱导的凋亡抗性。α5β1和GSK3β均可调控细胞外源性和内源性凋亡通路。我们的数据表明，在血清饥饿时，α5β1整合素参与可以通过激活GSK3β来调节特定的促生存功能。
Cell survival mediated by integrin engagement has been implicated in cell adhesion-mediated drug resistance. We have recently demonstrated that the activation of glycogen synthase kinase 3 β (GSK3β) is a new pathway supporting the chemoresistance of leukemic cells adhered to fibronectin. We show here that in conditions of serum starvation, the fibronectin receptor α5β1 integrin, but not α4β1, induced activation of GSK3β through Ser-9 dephosphorylation in adherent U937 cells. The GSK3β-dependent survival pathway occurred in adherent leukemic cells from patients but not in the HL-60 and KG1 cell lines. In adhesion, activated GSK3β was found in the cytosol/plasma membrane compartment and was co-immunoprecipitated with α5 integrin, the phosphatase PP2A and the scaffolding protein RACK1. PP2A and its regulatory subunit B' regulated the Ser-9 phosphorylation of GSK3β. In adherent leukemic cells, α5β1 integrin but not α4β1 upregulated the resistance to TNFα-induced apoptosis. Both extrinsic and intrinsic apoptotic pathways were under the control of α5β1 and GSK3β. Our data show that, upon serum starvation, α5β1 integrin engagement could regulate specific pro-survival functions through the activation of GSK3β.
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影响因子：
20.3
作者：
Kapur, R;Cooper, R;Williams, DA
通讯作者：
Williams, DA
影响因子：
11.2
作者：
Ougolkov, AV;Fernandez-Zapico, ME;Billadeau, DD
通讯作者：
Billadeau, DD
影响因子：
4.6
作者：
Deng, J;Xia, WY;Hung, MC
通讯作者：
Hung, MC
DOI：
10.2217/14796694.2.1.91
发表时间：
2006-02-01
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Ougolkov, Andrei V;Billadeau, Daniel D
通讯作者：
Billadeau, Daniel D
影响因子：
4.8
作者：
Kiely, PA;Leahy, M;O'Connor, R
通讯作者：
O'Connor, R