The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins
The ability of E1A to rescue ras-induced premature senescence and confer transformation relies on inactivation of both p300/CBP and Rb family proteins
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DOI：
10.1158/0008-5472.can-05-0054
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发表时间：
2005-09-15
期刊：
影响因子：
11.2
通讯作者：
Sun, PQ
中科院分区：
文献类型：
--
作者：
Deng, QD;Li, YL;Sun, PQ
在原代细胞中，致癌ras诱导稳定的生长停滞，称为过早衰老。ras诱导的过早衰老被认为是一种肿瘤抑制防御反应，需要绕过致癌潜力ras可以揭示。为了深入了解致癌转化过程中衰老旁路的机制，我们解剖了腺病毒癌蛋白E1 A的活性，该蛋白能够克服ras诱导的衰老。我们的结果表明。衰老旁路活性存在于NH 2末端，并且需要E1 A的Rb结合和p300/CBP结合功能。虽然干扰p16（INK 4A）/Rb通路或单独失活p300/CBP不会导致衰老旁路，但这两种类型的遗传改变分别补充了Rb结合缺陷型和p300/CBP结合缺陷型E1 A突变体，以挽救过早衰老。因此，破坏p16（INK 4A）/Rb通路或p300/ CBP功能的遗传改变都有助于绕过衰老。我们进一步表明p300/CBP是ras诱导的p53活性所必需的，提供了p300/CBP在衰老中的重要作用的潜在机制。此外，p300/CBP失活导致与p300/CBP结合缺陷型E1 A突变体MDM 2和Ha-RasV 12合作的细胞转化。这些结果表明，p300和CBP是介导ras诱导衰老的途径的组成部分。p300和CBP在限制ras致癌潜力的衰老反应中的关键作用为这些蛋白质的肿瘤抑制功能提供了机制基础。
In primary cells, oncogenic ras induces a stable growth arrest known as premature Senescence. Ras-induced premature senescence is considered as a tumor-suppressing defense response that needs to be bypassed before oncogenic potential ras can be revealed. To gain insights into the mechanism of senescence bypass during oncogenic transformation, we dissected the activities of an adenoviral oncoprotein E1A, which is capable of overcoming ras-induced senescence. Our results have indicated. that the senescence bypassing activity resides in the NH2 terminus and requires both Rb-binding and p300/CBP-binding functions of E1A. Although interference with the p16(INK4A)/Rb pathway or inactivation of p300/CBP alone did not lead to senescence bypass, these two types of genetic alterations complemented the Rb-binding defective and the p300/CBP-binding defective mutants of E1A, respectively, to rescue premature senescence. Therefore, genetic alterations disrupting the p16(INK4A)/Rb pathway or the p300/ CBP functions both contribute to the bypass of senescence. We further showed that p300/CBP were essential for ras-induced p53 activity, providing a potential mechanism underlying the important role of p300/CBP in senescence. Furthermore, p300/CBP inactivation led to cellular transformation in cooperation with the p300/CBP-binding defective E1A mutants, MDM2 and Ha-RasV12. These results have shown that p300 and CBP are integral components of the pathway that mediates ras-induced senescence. The critical role of p300 and CBP in the senescence response that limits the oncogenic potential of ras has provided a mechanistic basis for the tumor-suppressing function of these proteins.