Induction of sonic hedgehog mediators by transforming growth factor-β:: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo
Induction of sonic hedgehog mediators by transforming growth factor-β:: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo
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DOI：
10.1158/0008-5472.can-07-0491
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Mauviel, Alain
中科院分区：
文献类型：
--
作者：
Dennler, Sylviane;Andre, Jocelyne;Mauviel, Alain
Hedgehog（Hh）和转化生长因子-β（TGF-β）家族成员参与胚胎发育、毛发周期和癌症期间的许多重叠过程。在此，我们表明，TGF-β诱导Hh信号分子Gli 1和Gli 2在各种人类细胞类型，包括正常的成纤维细胞和角质形成细胞，以及各种癌细胞系的表达。由TGF-β诱导的Gli 2是快速的，独立于Hh受体信号传导，并且需要功能性Smad通路。Gli 1表达随后以Gli 2依赖性方式被激活。在皮肤中过度表达TGF-β 1的转基因小鼠中，Gli 1和Gli 2的表达也升高，并依赖于Smad 3。在对Hit抑制有抗性的胰腺癌细胞系中，TGF-β信号传导的药理学阻断导致细胞增殖的抑制，伴随着Gli 2表达的减少。因此，我们确定TGF-β作为Gli转录因子的有效转录诱导剂。针对Hh和TGF-β信号传导的合作可能为癌症治疗提供新的治疗机会。
Hedgehog (Hh) and transforming growth factor-beta (TGF-beta) family members are involved in numerous overlapping processes during embryonic development, hair cycle, and cancer. Herein, we show that TGF-beta induces the expression of the Hh signaling molecules Gli1 and Gli2 in various human cell types, including normal fibroblasts and keratinocytes, as well as various cancer cell lines. Gli2 induction by TGF-beta is rapid, independent from Hh receptor signaling, and requires a functional Smad pathway. Gli1 expression is subsequently activated in a Gli2-dependent manner. In transgenic mice overexpressing TGF-beta 1 in the skin, Gli1 and Gli2 expression is also elevated and depends on Smad3. In pancreatic adenocarcinoma cell lines resistant to Hit inhibition, pharmacologic blockade of TGF-beta signaling leads to repression of cell proliferation accompanied with a reduction in Gli2 expression. We thus identify TGF-beta as a potent transcriptional inducer of Gli transcription factors. Targeting the cooperation of Hh and TGF-beta signaling may provide new therapeutic opportunities for cancer treatment.