SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties
SOX9 inhibits β-TrCP-mediated protein degradation to promote nuclear GLI1 expression and cancer stem cell properties
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DOI：
10.1242/jcs.162164
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发表时间：
2015-03-15
影响因子：
4
通讯作者：
Ruppert, J. Michael
中科院分区：
文献类型：
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作者：
Deng, Wentao;Vanderbilt, Daniel B.;Ruppert, J. Michael
高迁移率族盒蛋白 SOX9 和 GLI1 转录因子在胰腺导管腺癌 (PDA) 中发挥促肿瘤作用。在 Kras 转基因小鼠中，这些因素中的每一个对于 PDA 前体病变的发展都至关重要。 SOX9 转录受 GLI1 直接调控，但 SOX9 如何在 GLI1 下游发挥作用尚不清楚。我们观察到正反馈，例如 SOX9 缺陷的 PDA 细胞严重抑制了内源性 GLI1 的水平，这归因于 GLI1 蛋白稳定性的丧失。 SOX9 与 SKP1/CUL1/F-box (SCF) E3 泛素连接酶成分 beta-TrCP（也称为含有 F-box/WD 重复序列的蛋白 1A）的 F-box 结构域相关，并抑制其与 SKP1 和 GLI1（SCF-beta-TrCP 的底物）的关联。 SOX9 还将 β-TrCP 束缚在细胞核内并促进其降解。 SOX9 通过介导转录激活的 SOX9 C 端 PQA/S 结构域与 β-TrCP 结合。在 SOX9 缺陷的 PDA 细胞中抑制 β-TrCP 可恢复 GLI1 水平并促进 SOX9 依赖性癌症干细胞特性。这些研究确定 SOX9-GLI1 正反馈是 GLI1 蛋白稳定性的主要决定因素，并表明 β-TrCP 作为潜在的 SOX9 结合肿瘤抑制因子，具有降解肿瘤细胞中致癌蛋白的潜力。
The high mobility group box protein SOX9 and the GLI1 transcription factor play protumorigenic roles in pancreatic ductal adenocarcinoma (PDA). In Kras transgenic mice, each of these factors are crucial for the development of PDA precursor lesions. SOX9 transcription is directly regulated by GLI1, but how SOX9 functions downstream of GLI1 is unclear. We observed positive feedback, such that SOX9-deficient PDA cells have severely repressed levels of endogenous GLI1, attributed to loss of GLI1 protein stability. SOX9 associated with the F-box domain of the SKP1/CUL1/F-box (SCF) E3 ubiquitin ligase component, beta-TrCP (also known as F-box/WD repeat-containing protein 1A), and suppressed its association with SKP1 and GLI1, a substrate of SCF-beta-TrCP. SOX9 also tethered beta-TrCP within the nucleus and promoted its degradation. SOX9 bound to beta-TrCP through the SOX9 C-terminal PQA/S domain that mediates transcriptional activation. Suppression of beta-TrCP in SOX9-deficient PDA cells restored GLI1 levels and promoted SOX9-dependent cancer stem cell properties. These studies identify SOX9-GLI1 positive feedback as a major determinant of GLI1 protein stability and implicate beta-TrCP as a latent SOX9-bound tumor suppressor with the potential to degrade oncogenic proteins in tumor cells.