Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2
Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2
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DOI：
10.1073/pnas.0712216105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Tanaka, Nobuyuki
中科院分区：
文献类型：
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作者：
Abe, Yoshinori;Oda-Sato, Eri;Tanaka, Nobuyuki
hedgehog （Hh）信号通路调节哺乳动物许多器官的发育，并且在人类癌症中广泛观察到该通路的激活。虽然已知Hh信号可以激活参与细胞生长的基因的表达，但Hh通路在癌症发展中的确切作用尚不清楚。在这里，我们发现Smoothened （Smo）的组成型激活突变体（Hh信号通路的换能器）抑制肿瘤抑制蛋白p53的积累。在Hh配体存在或Smo下游效应因子Gli1和Gli2过表达时也观察到这种抑制，表明这种抑制是Hh通路特异性的。我们还报道Smo突变体增强p53与E3泛素蛋白连接酶Mdm2的结合并促进p53泛素化。此外，Hh信号传导诱导人Mdm2蛋白在丝氨酸166和186上的磷酸化，这两个丝氨酸激活了Mdm2的磷酸化位点。Smo突变体在诱导dna损伤反应的同时增强了小鼠胚胎成纤维细胞（mef）的增殖。此外，Smo在表达癌基因的mef中部分抑制p53依赖性凋亡和细胞生长抑制。我们还发现，在几种人类癌细胞系中，Hh信号可以抑制p53的积累。因此，Hh通路可能通过激活细胞增殖和抑制p53介导的致癌应激诱导的抗癌屏障而成为肿瘤发生的强大加速器。
The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of Smoothened (Smo), a transducer of the Hh signaling pathway, inhibit the accumulation of the tumor suppressor protein p53. This inhibition was also observed in the presence of Hh ligand or with the overexpression of the transcription factors Gli1 and Gli2, downstream effectors of Smo, indicating that this inhibition is specific for the Hh pathway. We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. Furthermore, Hh signaling induced the phosphorylation of human Mdm2 protein on serines 166 and 186, which are activating phosphorylation sites of Mdm2. Smo mutants enhanced the proliferation of mouse embryonic fibroblasts (MEFs) while inducing a DNA-damage response. Moreover, Smo partially inhibited p53-dependent apoptosis and cell growth inhibition in oncogene-expressing MEFs. We also found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.