Gli1 inhibition suppressed cell growth and cell cycle progression and induced apoptosis as well as autophagy depending on ERK1/2 activity in human chondrosarcoma cells.
Gli1 inhibition suppressed cell growth and cell cycle progression and induced apoptosis as well as autophagy depending on ERK1/2 activity in human chondrosarcoma cells.
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Gli1 抑制抑制细胞生长和细胞周期进程，并根据人软骨肉瘤细胞中的 ERK1/2 活性诱导细胞凋亡和自噬
DOI：
10.1038/cddis.2013.497
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发表时间：
2014-01-02
影响因子：
9
通讯作者：
Yan, T.
中科院分区：
文献类型：
--
作者：
Sun, Y.;Guo, W.;Ren, T.;Liang, W.;Zhou, W.;Lu, Q.;Jiao, G.;Yan, T.
胶质瘤相关癌基因1（glioma-associated oncogene 1，Gli 1）是Hedgehog（Hh）信号通路的一个重要核执行子，在细胞形态形成、分化、增殖和凋亡等发育过程中发挥重要作用。patched 1蛋白和Gli 1的过表达或组成性激活的印度刺猬（IHh）-甲状旁腺相关蛋白信号通路可能导致肌肉骨骼肿瘤的发生。然而，对于软骨肉瘤，很少有研究密切关注IHh-Gli 1信号转导级联，需要进行更多的工作，以充分阐明Gli 1蛋白的功能。我们发现软骨肉瘤中的IHh信号通路被激活，Gli 1表达下调可减弱IHh信号通路的紊乱，这不仅抑制细胞增殖，促进G2/M期细胞阻滞，而且通过下调Bcl-2和Bcl-xl的表达促进细胞凋亡。此外，Gli 1下调，而不是环巴胺，诱导自噬通过调节mTOR磷酸化，抑制自噬阻止Gli 1小干扰RNA介导的细胞死亡。我们还表明，细胞外信号调节激酶1/2的活性可能介导的Gli 1抑制诱导的这些抗增殖事件。这些结果表明，Gli 1抑制可能最终为软骨肉瘤治疗提供一种有前途的新方法。
The transcription factor glioma-associated oncogene 1 (Gli1) has been recognized as a very important nuclear executor at the distal end of the Hedgehog (Hh) signal pathway, which has crucial roles in regulating many developmental processes, such as pattern formation, differentiation, proliferation, and apoptosis. Overexpression of patched 1 protein and Gli1 or constitutively active Indian Hedgehog (IHh)-parathyroid hormone-related protein signal pathway may lead to musculoskeletal tumorigenesis. However, for chondrosarcoma few studies have paid close attention to the IHh-Gli1 signal transduction cascade and more work needs to be carried out to fully elucidate Gli1 protein functions. Here we show that the IHh signal pathway was activated in chondrosarcoma, and knocking down the expression of Gli1 attenuated the disturbed IHh signal pathway, which not only suppressed cell proliferation and promoted G2/M cell cycle arrest but also enhanced cell apoptosis by downregulating Bcl-2 and Bcl-xl expression. Furthermore, Gli1 downregulation, not cyclopamine, induced autophagy by regulating mTOR phosphorylation, and inhibition of autophagy prevented Gli1 small interfering RNA-mediated cell death. We also demonstrated that extracellular signal-regulated kinase 1/2 activity may mediate these antiproliferative events induced by Gli1 inhibition. These results indicate that Gli1 inhibition could ultimately provide a promising new approach for chondrosarcoma treatment.
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DOI：
10.1016/s0190-9622(97)70145-2
发表时间：
1997-09-01
影响因子：
13.8
作者：
Barrett, TL;Smith, KJ;Skelton, HG
通讯作者：
Skelton, HG
影响因子：
4.4
作者：
Kohno, M;Pouyssegur, J
通讯作者：
Pouyssegur, J
DOI：
10.1083/jcb.38.2.377
发表时间：
1968-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fedorko ME;Hirsch JG;Cohn ZA
通讯作者：
Cohn ZA
影响因子：
4.9
作者：
Alvarez, Rene;Elbashir, Sayda;Meyers, Rachel
通讯作者：
Meyers, Rachel
影响因子：
56.9
作者：
Lanske, B;Karaplis, AC;Kronenberg, HM
通讯作者：
Kronenberg, HM