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首页> 外文期刊>Molecular and Cellular Biology >Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity
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Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity

机译：Axl-Gas6相互作用抵消E1A介导的细胞生长抑制和促凋亡活性。

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The adenovirus type 5 early region 1A gene (E1A) has previously been known as an immortalization oncogene because E1A is required for transforming oncogenes, such as ras andE1B, to transform cells in primary cultures. However, E1A has also been shown to downregulate the overexpression of theHer-2eu oncogene, resulting in suppression of transformation and tumorigenesis induced by that oncogene. In addition, E1A is able to promote apoptosis induced by anticancer drugs, irradiation, and serum deprivation. Many tyrosine kinases, such as the epidermal growth factor receptor, Her-2/Neu, Src, and Axl, are known to play a role in oncogenic signals in transformed cells. To study the mechanism underlying the E1A-mediated tumor-suppressing function, we exploited a modified tyrosine kinase profile assay (D. Robinson, F. Lee, T. Pretlow, and H.-J. Kung, Proc. Natl. Acad. Sci. USA 93:5958–5962, 1996) to identify potential tyrosine kinases regulated by E1A. Reverse transcription (RT)-PCR products were synthesized with two degenerate primers derived from the conserved motifs of various tyrosine kinases. A tyrosine kinase downregulated by E1A was identified by analyzing the AluI-digested RT-PCR products. We isolated the DNA fragment of interest and found that E1A negatively regulated the expression of the transforming receptor tyrosine kinase Axl at the transcriptional level. To study whether downregulation of the Axl receptor is involved in E1A-mediated growth suppression, we transfectedaxl cDNA into E1A-expressing cells (ip1-E1A) to establish cells that overexpressed Axl. The Axl ligand Gas6 triggered a greater mitogenic effect in these ip1-E1A-Axl cells than in ip1-E1A control cells and protected the Axl-expressing cells from serum deprivation-induced apoptosis. These results indicate that downregulation of the Axl receptor by E1A is involved in E1A-mediated growth suppression and E1A-induced apoptosis and thereby contributes to E1A’s antitumor activities.
机译：腺病毒5型早期区域1A基因（ E1A ）以前被称为永生化癌基因，因为转化E.A基因（例如 ras 和 E1B < / em>，以转化原代培养物中的细胞。然而，还显示E1A下调了 Her-2 / neu 癌基因的过表达，导致该癌基因诱导的转化和肿瘤发生受到抑制。此外，E1A能够促进抗癌药，放射线和血清剥夺诱导的细胞凋亡。已知许多酪氨酸激酶，例如表皮生长因子受体，Her-2 / Neu，Src和Axl在转化细胞的致癌信号中起作用。为了研究潜在的E1A介导的肿瘤抑制功能的机制，我们利用了改良的酪氨酸激酶谱分析（D. Robinson，F。Lee，T。Pretlow和H.-J. Kung，Proc。Natl。Acad。Sci （美国93：5958-5596，1996），以鉴定受E1A调节的潜在酪氨酸激酶。用两种衍生自各种酪氨酸激酶保守基序的简并引物合成了逆转录（RT）-PCR产物。通过分析 Alu I消化的RT-PCR产物鉴定出被E1A下调的酪氨酸激酶。我们分离了感兴趣的DNA片段，发现E1A在转录水平上负调控转化受体酪氨酸激酶Axl的表达。为了研究Axl受体的下调是否参与E1A介导的生长抑制，我们将 axl cDNA转染到表达E1A的细胞（ip1-E1A）中，以建立过度表达Axl的细胞。与ip1-E1A对照细胞相比，Axl配体Gas6在这些ip1-E1A-Axl细胞中引发了更大的促有丝分裂作用，并保护了表达Axl的细胞免于血清剥夺诱导的细胞凋亡。这些结果表明，E1A对Axl受体的下调与E1A介导的生长抑制和E1A诱导的细胞凋亡有关，从而有助于E1A的抗肿瘤活性。

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