Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor
Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14ARF tumor suppressor
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DOI：
10.1128/mcb.20.1.273-285.2000
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发表时间：
2000-01-01
影响因子：
5.3
通讯作者：
Campisi, J
中科院分区：
文献类型：
--
作者：
Dimri, GP;Itahana, K;Campisi, J
正常细胞不会无限期地分裂，这是由于一个被称为复制性衰老的过程。当人类细胞由于细胞分裂而获得一个或多个非常短的端粒时，它们会以衰老表型阻止生长。最近的证据表明，某些类型的DNA损伤、染色质重塑和Ras或Raf的致癌形式也可以引起衰老反应。我们在这里表明，E2F1，一个多功能的转录因子，结合视网膜母细胞瘤（pRb）肿瘤抑制因子，可以促进或抑制肿瘤发生，诱导衰老表型时，在正常人成纤维细胞过表达。正常人细胞稳定地抑制增殖，并表达几种复制性衰老的标志物，以响应E2F1。E2F1的这种活性不依赖于其pRb结合活性，而是依赖于其刺激基因表达的能力。衰老反应的关键E2F1靶基因似乎是p14（ARF）肿瘤抑制因子。复制衰老的人成纤维细胞过表达p14（ARF），和异位表达p14（ARF）在衰老细胞诱导的表型相似的诱导E2F1。与p14（ARF）的关键作用一致，p53功能受损的细胞对E2F1的衰老诱导免疫，p14（ARF）缺陷的细胞也是如此。我们的研究结果支持衰老反应是一个重要的肿瘤抑制机制的想法，提供了一个解释E2F1在肿瘤发生中的明显矛盾的作用，并确定p14（ARF）作为一个潜在的重要介质的衰老表型。
Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomeres as a consequence of cell division. Recent evidence suggests that certain: types:of DNA damage, chromatin remodeling, and oncogenic forms of Ras or Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and that can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14(ARF) tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14(ARF), and ectopic expression of p14(ARF) in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14(ARF), cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14(ARF). Our findings support the idea that the senescence response is a critical tumor-suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14(ARF) as a potentially important mediator of the senescent phenotype.