Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development
Expression of the Arf tumor suppressor gene is controlled by Tgfβ2 during development
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DOI：
10.1242/dev.033548
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发表时间：
2009-06-15
期刊：
影响因子：
4.6
通讯作者：
Skapek, Stephen X.
中科院分区：
文献类型：
--
作者：
Freeman-Anderson, Natalie E.;Zheng, Yanbin;Skapek, Stephen X.
Arf肿瘤抑制因子（也称为Cdkn2a）作为癌基因传感器，在早期癌细胞中由“异常”有丝分裂信号诱导。它在胚胎发育中也起着至关重要的作用：缺乏Arf的新生小鼠由于一种类似于严重持续性增殖性原发性玻璃体（PHPV）的病理过程而失明，这是一种人类眼病。癌基因传感器模型中隐含的细胞内在机制似乎不太可能解释胚胎发育过程中Arf的调控。相反，转化生长因子β 2 （Tgf β 2）可能控制Arf的表达，因为我们发现缺乏Tgf β 2的小鼠与Arf（-/-）小鼠相似，具有原发性玻璃体增生。与潜在的线性途径一致，Tgf β 2诱导培养的小鼠胚胎成纤维细胞（mef）中Arf转录和p19（Arf）表达；Tgf β 2依赖性细胞周期阻滞在MEFs中以arf依赖性的方式维持。在Arf（lacZ/+）小鼠中通过β -半乳糖苷酶活性追踪Arf表达的新模型中，我们发现在发育中的玻璃体以及角膜和脐动脉中，Tgf β 2是Arf转录所必需的，而这两个位点以前未被识别为Arf表达的位点。化学和遗传策略表明，Arf启动子的诱导依赖于Tgf β受体对Smad蛋白的激活；这种诱导与体内mef和arf表达细胞中的Smad2磷酸化有关。染色质免疫沉淀显示Smads结合到Arf外显子1 β附近的基因组DNA上。综上所述，Tgf β 2和p19（Arf）在胚胎发育过程中以线性途径起作用。我们首次提出了p19（Arf）表达可与正常细胞外信号偶联的证据，并提出了肿瘤细胞中Arf控制的新机制。
The Arf tumor suppressor ( also known as Cdkn2a) acts as an oncogene sensor induced by 'abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological process resembling severe persistent hyperplastic primary vitreous ( PHPV), a human eye disease. The cell-intrinsic mechanism implied in the oncogene sensor model seems unlikely to explain Arf regulation during embryo development. Instead, transforming growth factor beta 2 (Tgf beta 2) might control Arf expression, as we show that mice lacking Tgf beta 2 have primary vitreous hyperplasia similar to Arf(-/-) mice. Consistent with a potential linear pathway, Tgf beta 2 induces Arf transcription and p19(Arf) expression in cultured mouse embryo fibroblasts (MEFs); and Tgf beta 2-dependent cell cycle arrest in MEFs is maintained in an Arf-dependent manner. Using a new model in which Arf expression can be tracked by beta-galactosidase activity in Arf(lacZ/+) mice, we show that Tgf beta 2 is required for Arf transcription in the developing vitreous as well as in the cornea and the umbilical arteries, two previously unrecognized sites of Arf expression. Chemical and genetic strategies show that Arf promoter induction depends on Tgf beta receptor activation of Smad proteins; the induction correlates with Smad2 phosphorylation in MEFs and Arf-expressing cells in vivo. Chromatin immunoprecipitation shows that Smads bind to genomic DNA proximal to Arf exon 1 beta. In summary, Tgf beta 2 and p19(Arf) act in a linear pathway during embryonic development. We present the first evidence that p19(Arf) expression can be coupled to extracellular cues in normal cells and suggest a new mechanism for Arf control in tumor cells.