Laner-Plamberger S, Kaser A, Paulischta M, Hauser-Kronberger C, Eichberger T, Frischauf A M
Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
Oncogene. 2009 Apr 2;28(13):1639-51. doi: 10.1038/onc.2009.10. Epub 2009 Feb 16.
Sustained Hedgehog (HH) signaling is implicated in basal cell carcinoma of the skin and other types of cancer. Here we show that GLI1 and GLI2, the main transcriptional activators of the HH pathway, directly regulate expression of the activator protein 1 (AP-1) family member JUN, a transcription factor controlling keratinocyte proliferation and skin homeostasis. Activation of the JUN promoter by GLI is dependent on a GLI-binding site and the AP-1 sites known to be involved in self-activation of JUN. Transcription of JUN is greatly enhanced in the presence of GLI and requires activated JUN protein. GLI2act is a more potent activator than GLI1 in these experiments and physical interaction with phosphorylated JUN was only detected for GLI2act. The synergistic effect of GLI and JUN extends to the activation of further GLI target genes as shown by shRNA-mediated knockdown of JUN in human keratinocytes. Some of these cooperatively activated genes are involved in cell-cycle progression, which is consistent with a significant reduction of the proliferative potential of GLI in the absence of JUN. These results suggest a novel connection between HH/GLI pathway activity and JUN, which may contribute to the oncogenic activity of HH/GLI signaling in skin.
持续的刺猬信号通路（HH）与皮肤基底细胞癌及其他类型的癌症有关。在此我们表明，HH通路的主要转录激活因子GLI1和GLI2直接调控激活蛋白1（AP-1）家族成员JUN的表达，JUN是一种控制角质形成细胞增殖和皮肤稳态的转录因子。GLI对JUN启动子的激活依赖于一个GLI结合位点以及已知参与JUN自身激活的AP-1位点。在存在GLI的情况下，JUN的转录显著增强，并且需要激活的JUN蛋白。在这些实验中，GLI2act比GLI1是更强效的激活因子，并且仅检测到GLI2act与磷酸化JUN存在物理相互作用。如在人角质形成细胞中通过短发夹RNA（shRNA）介导的JUN敲低所示，GLI和JUN的协同作用扩展到进一步的GLI靶基因的激活。这些协同激活的基因中有一些参与细胞周期进程，这与在没有JUN的情况下GLI增殖潜力的显著降低是一致的。这些结果表明HH/GLI通路活性与JUN之间存在一种新的联系，这可能有助于HH/GLI信号在皮肤中的致癌活性。
