TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells
TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells
复制标题
DOI：
10.1016/j.mce.2013.06.033
复制
发表时间：
2013-09-05
影响因子：
4.1
通讯作者：
Baxter, Robert C.
中科院分区：
文献类型：
--
作者：
Schedlich, Lynette J.;Yenson, Vanessa M.;Baxter, Robert C.
由转化生长因子-β（TGF-β）和胰岛素样生长因子（IGF）启动的信号通路在骨肉瘤细胞生长中是重要的。我们研究了内源性IGF结合蛋白-3（IGFBP-3）在MG-63骨肉瘤细胞中介导TGF-β受体和I型IGF受体（IGF 1 R）信号通路之间的串扰中的作用。TGF-β 1间接激活Ras/Raf/MAPK通路并诱导IGFBP-3的表达，IGFBP-3是IGF 1 R活性的重要调节因子。IGFBP-3可抑制MG-63细胞中TGF-β 1对ERK 1/2和Akt的激活，并抑制TGF-β 1诱导的细胞周期进程和增殖。IGFBP-3的这种作用通过抑制IGF 1 R信号传导而被阻断。TGF-β 1在非受体底物位点（Ser 245/250/255）磷酸化Smad 2。阻断TGF-β 1诱导的IGFBP-3表达增强了pSmad 2（Ser 245/250/255）并增加了其核积聚。这些结果表明TGF-β 1在骨肉瘤细胞生长中的重要作用，TGF-β 1诱导IGFBP-3在负反馈回路中起作用，通过阻止IGF 1 R的激活来控制细胞生长。(c)2013爱思唯尔爱尔兰有限公司版权所有。
Signaling pathways initiated by transforming growth factor-beta (TGF-beta) and insulin-like growth factors (IGFs) are important in osteosarcoma cell growth. We have investigated a role for endogenous IGF binding protein-3 (IGFBP-3) in mediating cross-talk between TGF-beta receptor and type I IGF receptor (IGF1R) signaling pathways in MG-63 osteosarcoma cells. TGF-beta 1 indirectly activated the Ras/Raf/MAPK pathway and induced the expression of IGFBP-3, an important regulator of IGF1R activity. IGFBP-3 attenuated TGF-beta 1 activation of ERK1/2 and Akt in MG-63 cells, and inhibited TGF-beta 1-induced cell cycle progression and proliferation. This effect of IGFBP-3 was blocked by inhibiting IGF1R signaling. TGF-beta 1 phosphorylated Smad2 on the non-receptor substrate sites (Ser245/250/255). Blocking the TGF-beta 1-induced expression of IGFBP-3 enhanced pSmad2(Ser245/250/255) and increased its nuclear accumulation. These results suggest an important role for TGF-beta 1 in osteosarcoma cell growth, with the induction of IGFBP-3 by TGF-beta 1 serving in a negative-feedback loop to control cell growth by preventing activation of the IGF1R. (c) 2013 Elsevier Ireland Ltd. All rights reserved.