Oncogenic activity of Cdc6 through repression of the INK4/ARF locus (Retracted article. See vol. 547, pg. 246, 2017)
Oncogenic activity of Cdc6 through repression of the INK4/ARF locus (Retracted article. See vol. 547, pg. 246, 2017)
复制标题
DOI：
10.1038/nature04585
复制
发表时间：
2006-03-30
期刊：
影响因子：
64.8
通讯作者：
Serrano, M
中科院分区：
文献类型：
--
作者：
Gonzalez, S;Klatt, P;Serrano, M
INK 4/ARF基因座编码三种肿瘤抑制因子（p15（INK 4 b）、ARF和p16（INK 4a）），是人类癌症中最常失活的基因座之一（1，2）。然而，人们对控制该位点表达的机制知之甚少。在这里，我们已经确定了一个假定的DNA复制起点在INK 4/ARF基因座，组装一个多蛋白复合物包含Cdc 6，Orc 2和MCMs，并符合保守的非编码DNA元件（调节域RDINK 4/ARF）。靶向和定位RNA干扰诱导的RDINK 4/ARF异染色质化导致该位点的转录抑制，揭示RDINK 4/ARF是相关的转录调控元件。Cdc 6在人类癌症中过表达，在那里它可能除了DNA复制之外还发挥作用（3-5）。我们已经发现，高水平的Cdc 6导致RDINK 4/ARF依赖的转录抑制，组蛋白脱乙酰基酶的招募和INK 4/ARF位点的异染色质化，以及伴随的由该位点编码的三种肿瘤抑制因子的表达减少。这种机制让人想起酵母中交配型HM基因座被复制因子沉默（6）。与其抑制INK 4/ARF位点的能力一致，Cdc 6具有细胞永生化活性和与致癌Ras合作的肿瘤转化能力。此外，具有高水平Cdc 6的人肺癌与低水平p16（INK 4a）相关。我们的结论是，Cdc 6的异常表达是致癌的直接抑制INK 4/ARF基因座通过RDINK 4/ARF元件。
The INK4/ARF locus encodes three tumour suppressors (p15(INK4b), ARF and p16(INK4a)) and is among the most frequently inactivated loci in human cancer(1,2). However, little is known about the mechanisms that govern the expression of this locus. Here we have identified a putative DNA replication origin at the INK4/ARF locus that assembles a multiprotein complex containing Cdc6, Orc2 and MCMs, and that coincides with a conserved noncoding DNA element ( regulatory domain RDINK4/ARF). Targeted and localized RNA-interference-induced heterochromatinization of RDINK4/ARF results in transcriptional repression of the locus, revealing that RDINK4/ARF is a relevant transcriptional regulatory element. Cdc6 is overexpressed in human cancers, where it might have roles in addition to DNA replication(3-5). We have found that high levels of Cdc6 result in RDINK4/ARF-dependent transcriptional repression, recruitment of histone deacetylases and heterochromatinization of the INK4/ARF locus, and a concomitant decrease in the expression of the three tumour suppressors encoded by this locus. This mechanism is reminiscent of the silencing of the mating-type HM loci in yeast by replication factors(6). Consistent with its ability to repress the INK4/ARF locus, Cdc6 has cellular immortalization activity and neoplastic transformation capacity in cooperation with oncogenic Ras. Furthermore, human lung carcinomas with high levels of Cdc6 are associated with low levels of p16(INK4a). We conclude that aberrant expression of Cdc6 is oncogenic by directly repressing the INK4/ARF locus through the RDINK4/ARF element.