HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas (Retracted article. See vol. 78, pg. 6906, 2018)
HMGA Proteins Up-regulate CCNB2 Gene in Mouse and Human Pituitary Adenomas (Retracted article. See vol. 78, pg. 6906, 2018)
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DOI：
10.1158/0008-5472.can-08-4133
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Fusco, Alfredo
中科院分区：
文献类型：
--
作者：
De Martino, Ivana;Visone, Rosa;Fusco, Alfredo
高迁移率族As（HMGAs）属于非组蛋白核蛋白家族，其协调核蛋白复合物的组装。通过蛋白质-DNA和蛋白质-蛋白质相互作用的复杂网络，它们在基因转录、重组和染色质结构中发挥重要作用。该蛋白质家族通过不同的机制参与良性和恶性肿瘤。我们最近报道，转基因小鼠携带Hmga 1或Hmga 2基因的巨细胞病毒启动子的转录控制下发展垂体腺瘤分泌催乳素和生长激素。我们已经表明，RMGA 2诱导的垂体腺瘤的机制是基于E2 F1活性的增加。在HMGA转基因小鼠中诱导的小鼠正常垂体腺和腺瘤的表达谱显示，与正常垂体腺相比，在肿瘤组织中编码细胞周期蛋白B2蛋白的ccnb 2基因的表达增加。在这里，我们显示，通过电泳迁移率变动分析和染色质免疫沉淀，HMGA蛋白的ccnb 2基因的启动子的直接结合，而荧光素酶分析表明，HMGA能够上调ccnb 2启动子活性。最后，我们报告了CCNB 2在不同组织型的人垂体腺瘤中的表达增加，这与HMGA 1和HMGA 2的表达直接相关。由于细胞周期蛋白B2参与细胞周期的调控，这些结果共同表明，HMGA诱导的细胞周期蛋白B2过表达实验和人类垂体肿瘤的发生提供了重要的贡献。[Cancer Res 2009;69（5）：1844-50]
The high mobility group As (HMGAs) belong to a family of nonhistone nuclear proteins that orchestrate the assembly of nucleoprotein complexes. Through a complex network of protein-DNA and protein-protein interaction, they play important roles in gene transcription, recombination, and chromatin structure. This protein family is involved, through different mechanisms, in both benign and malignant neoplasias. We have recently reported that transgenic mice carrying the Hmga1 or Hmga2 genes under transcriptional control of the cytomegalovirus promoter develop pituitary adenomas secreting prolactin and growth hormone. We have shown that the mechanism of the RMGA2-induced pituitary adenoma is based on the increased E2F1 activity. The expression profile of mouse normal pituitary glands and adenomas induced in HMGA transgenic mice revealed an increased expression of the ccnb2 gene, coding for the cyclin B2 protein, in the neoplastic tissues compared with the normal pituitary gland. Here, we show, by electrophoretic mobility shift assay and chromatin immunoprecipitation, a direct binding of HMGA proteins to the promoter of ccnb2 gene, whereas luciferase assays showed that HMGAs are able to up-regulate ccnb2 promoter activity. Finally, we report an increased CCNB2 expression in human pituitary adenomas of different histotypes that is directly correlated with HMGA1 and HMGA2 expression. Because cyclin B2 is involved in the regulation of the cell cycle, these results taken together indicate that HMGA-induced cyclin B2 overexpression gives an important contribution to experimental and human pituitary tumorigenesis. [Cancer Res 2009;69(5):1844-50]