Rahnama Fahimeh, Shimokawa Takashi, Lauth Matthias, Finta Csaba, Kogerman Priit, Teglund Stephan, Toftgård Rune, Zaphiropoulos Peter G
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
Biochem J. 2006 Feb 15;394(Pt 1):19-26. doi: 10.1042/BJ20050941.
Patched1 (PTCH1) is a human tumour suppressor that acts as an HH (Hedgehog) receptor protein and is important for embryonic patterning. PTCH1 mediates its effects through SMO (Smoothened) and represses the expression of HH target genes such as the transcription factor GLI1 (glioma 1) as well as PTCH1. Up-regulation of these genes has been observed in several cancer forms, including basal cell carcinoma, digestive track tumours and small cell lung cancer. The fact that PTCH1 down-regulates its own expression via 'negative feedback' is an important feature in HH signalling, as it keeps the balance between HH and PTCH1 activities that are essential for normal development. In the present study, we provide evidence that a novel mechanism allowing PTCH1 to maintain this balance may also exist. We show that gene activation by GLI1, the transcriptional effector of the pathway, can be down-regulated by PTCH1 without involvement of the canonical cascade of HH signalling events. Specifically, the SMO antagonist cyclopamine has no appreciable effects in blocking this PTCH1-mediated inhibition. Moreover, the negative GLI1 regulator SUFU (Suppressor of Fused) was also found to be dispensable. Additionally, deletion mapping of PTCH1 has revealed that the domains encompassed by amino acids 180-786 and 1058-1210 are of highest significance in inhibiting GLI1 gene activation. This contrasts with the importance of the PTCH1 C-terminal domain for HH signalling.
patched1（PTCH1）是一种人类肿瘤抑制因子，作为一种HH（刺猬）受体蛋白，对胚胎模式形成很重要。PTCH1通过SMO（平滑）介导其作用，并抑制HH靶基因的表达，如转录因子GLI1（胶质瘤1）以及PTCH1。在几种癌症类型中都观察到了这些基因的上调，包括基底细胞癌、消化道肿瘤和小细胞肺癌。PTCH1通过“负反馈”下调自身表达这一事实是HH信号传导中的一个重要特征，因为它保持了HH和PTCH1活性之间的平衡，而这种平衡对于正常发育至关重要。在本研究中，我们提供证据表明，可能还存在一种允许PTCH1维持这种平衡的新机制。我们表明，该信号通路的转录效应因子GLI1介导的基因激活可被PTCH1下调，而无需HH信号传导事件的经典级联反应参与。具体而言，SMO拮抗剂环杷明在阻断这种PTCH1介导的抑制作用方面没有明显效果。此外，还发现负性GLI1调节因子SUFU（融合抑制因子）也是可有可无的。此外，PTCH1的缺失图谱分析表明，氨基酸180 - 786和1058 - 1210所包含的结构域在抑制GLI1基因激活方面具有最高的重要性。这与PTCH1 C末端结构域对HH信号传导的重要性形成对比。
