TGFBI deficiency predisposes mice to spontaneous tumor development.
TGFBI deficiency predisposes mice to spontaneous tumor development.
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TGFBI 缺乏使小鼠容易自发形成肿瘤。
DOI：
10.1158/0008-5472.can-08-1648
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发表时间：
2009-01-01
期刊：
影响因子：
11.2
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Zhang Y;Wen G;Shao G;Wang C;Lin C;Fang H;Balajee AS;Bhagat G;Hei TK;Zhao Y
体外研究表明，转化生长因子-β诱导的分泌蛋白TGFBI的缺失与细胞增殖、肿瘤进展和血管生成有关。然而，TGFBI的体内抗肿瘤功能以及潜在的分子机制还不清楚。为了这些目的，我们已经产生了具有TGFBI基因组位点破坏的小鼠模型。缺乏TGFBI的小鼠表现出生长迟缓，并且易于发生自发性肿瘤和7，12-二甲基苯并（a）蒽诱导的皮肤肿瘤。与野生型（WT）小鼠胚胎成纤维细胞（MEF）相比，TGFBI（-/-）MEF显示染色体畸变和微核形成频率增加，并表现出增殖增强和早期S期进入。细胞周期蛋白D1在TGFBI（-/-）MEFs中上调，这与通过染色质免疫沉淀和荧光素酶报告基因测定鉴定的转录因子环AMP反应元件结合蛋白（CREB）的异常激活相关。通过逆转录病毒感染WT TGFBI基因或在培养基中补充重组小鼠TGFBI蛋白在TGFBI（-/-）细胞中重建TGFBI导致CREB活化和细胞周期蛋白D1表达的抑制，并进一步抑制细胞增殖。在TGFBI（-/-）小鼠产生的大多数肿瘤中也发现了细胞周期蛋白D1的上调。我们的研究提供了第一个证据表明，TGFBI功能作为一种肿瘤抑制剂在体内。
Loss of TGFBI, a secreted protein induced by transforming growth factor-beta, has been implicated in cell proliferation, tumor progression, and angiogenesis by in vitro studies. However, in vivo antitumor functions of TGFBI as well as the underlying molecular mechanism are not well understood. To these aims, we have generated a mouse model with disruption of TGFBI genomic locus. Mice lacking TGFBI show a retarded growth and are prone to spontaneous tumors and 7,12-dimethylbenz(a)anthracene-induced skin tumors. In relation to wild-type (WT) mouse embryonic fibroblasts (MEF), TGFBI(-/-) MEFs display increased frequencies of chromosomal aberration and micronuclei formation and exhibit an enhanced proliferation and early S-phase entry. Cyclin D1 is up-regulated in TGFBI(-/-) MEFs, which correlates with aberrant activation of transcription factor cyclic AMP-responsive element binding protein (CREB) identified by chromatin immunoprecipitation and luciferase reporter assays. TGFBI reconstitution in TGFBI(-/-) cells by either retroviral infection with WT TGFBI gene or supplement with recombinant mouse TGFBI protein in the culture medium leads to the suppression of CREB activation and cyclin D1 expression, and further inhibition of cell proliferation. Cyclin D1 up-regulation was also identified in most of the tumors arising from TGFBI(-/-) mice. Our studies provide the first evidence that TGFBI functions as a tumor suppressor in vivo.