The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.
The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.
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DOI：
10.1210/en.2013-1646
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发表时间：
2014-04
期刊：
影响因子：
4.8
通讯作者：
McCabe CJ
中科院分区：
文献类型：
--
作者：
Read ML;Seed RI;Fong JC;Modasia B;Ryan GA;Watkins RJ;Gagliano T;Smith VE;Stratford AL;Kwan PK;Sharma N;Dixon OM;Watkinson JC;Boelaert K;Franklyn JA;Turnell AS;McCabe CJ
pttg1结合因子（PBF/PTTG1IP）作为原癌基因在甲状腺生物学中发挥着重要的作用。在人甲状腺癌中，高PBF表达与不良预后和较低的疾病特异性生存率独立相关。然而，PBF在甲状腺肿瘤发生中的确切作用尚不清楚。在这里，我们提供了大量的证据表明PBF是p53的一种新的调节因子，p53是一种肿瘤抑制蛋白，在维持遗传稳定性方面起关键作用，在分化型甲状腺癌中很少发生突变。通过共免疫沉淀和接近结扎实验，我们发现PBF特异性结合甲状腺细胞中的p53，并显著抑制应答启动子的反激活。此外，我们发现PBF通过增强泛素化来降低p53的稳定性，泛素化似乎依赖于Mdm2的E3连接酶活性。在甲状腺特异性PBF过表达（PBF- tg）的转基因小鼠模型中，p53功能明显受损，FISSR-PCR分析表明，PBF- tg显著增加了遗传不稳定性。与此一致的是，在PBF-Tg原代培养物中，约40%的DNA修复基因被抑制，包括在维持基因组完整性中起关键作用的基因，如Mgmt、Rad51和Xrcc3。我们的数据还显示，PBF诱导导致小鼠甲状腺细胞中E2酶Rad6的上调，并与人类甲状腺肿瘤中Rad6的表达相关。总的来说，这项工作为原癌基因PBF作为p53功能的负调节因子在甲状腺肿瘤发生中的作用提供了新的见解，与其他肿瘤类型相比，PBF通常过表达，p53突变罕见。
The PTTG1-Binding Factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a proto-oncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity ligation assays, we show that PBF binds specifically to p53 in thyroid cells, and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF over-expression (PBF-Tg), which had significantly increased genetic instability as indicated by FISSR-PCR analysis. Consistent with this, ~40% of all DNA repair genes examined were repressed in PBF-Tg primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51 and Xrcc3. Our data also revealed that PBF induction resulted in upregulation of the E2 enzyme Rad6 in murine thyrocytes, and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the proto-oncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, where PBF is generally over-expressed and p53 mutations are rare compared to other tumor types.
人甲状腺癌细胞是具有或不具有功能性p53的同类基因，等型细胞系的来源。
影响因子：
8.8
作者：
Wyllie, FS;Haughton, MF;Rowson, JM;Wynford-Thomas, D
通讯作者：
Wynford-Thomas, D