Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice
Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice
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DOI：
10.1038/sj.onc.1205050
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发表时间：
2002-02-07
期刊：
影响因子：
8
通讯作者：
Overbeek, PA
中科院分区：
文献类型：
--
作者：
Chen, Q;Ash, JD;Overbeek, PA
以往的研究表明腺病毒E1A癌蛋白可以与视网膜母细胞瘤肿瘤抑制蛋白（retinoblastoma tumor suppressor protein，pRb）和转录辅激活因子CBP/p300结合并结合。在这项研究中，野生型E1A12S或两个缺失突变体（delN.其结合pRb但不结合CBP/p300; delCR2。其结合CBP/p300但不结合pRb）与晶状体特异性α A-晶状体蛋白启动子连接，并用于产生转基因小鼠。表达E1 A12 S或delCR 2的透镜纤维细胞不能上调β-晶状体蛋白和γ-晶状体蛋白的表达，两者都与CBP/p300结合。相反，表达delN的透镜纤维细胞显示β-和γ-晶体蛋白的显著表达。表达delN的透镜纤维细胞显示细胞周期进入、显著的细胞凋亡和p53激活的证据，而表达E1A12 S或delCR 2的细胞显示有限的细胞凋亡并且没有p53诱导基因p21上调的证据。我们的研究结果表明，转录辅激活因子CBP和/或p300所需的晶体蛋白的表达，伴随终末分化的透镜中的显着增加，也为激活p53在透镜中的pRb的失活。
Previous studies have shown that the adenovirus E1A oncoprotein can bind to and inactivate the retinoblastoma tumor suppressor protein (pRb) and the transcriptional coactivators CBP/p300. In this study, wild-type E1A12S or two deletion mutants (delN. which binds pRb but not CBP/p300; delCR2. which binds to CBP/p300 but not pRb) were linked to the lens-specific alphaA-crystallin promoter, and used to generate transgenic mice. Lens fiber cells expressing E1A12S or delCR2, both of which bind to CBP/p300, failed to upregulate beta-crystallin and gamma-crystallin expression. In contrast, lens fiber cells expressing delN showed significant expression of beta- and gamma-crystallins. Lens fiber cells expressing delN showed cell cycle entry, marked apoptosis, and evidence for p53 activation, while cells expressing either E1A12S or delCR2 showed limited apoptosis and no evidence for upregulation of the p53-inducible gene p21. Our results suggest that the transcriptional coactivators CBP and/or p300 are required for the dramatic increases in crystallin expression that accompany terminal differentiation in the lens, and also for activation of p53 in response to inactivation of pRb in the lens.