Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro
Cytoplasmic p27 is oncogenic and cooperates with Ras both in vivo and in vitro
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DOI：
10.1038/onc.2011.9
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Besson, A.
中科院分区：
文献类型：
--
作者：
Serres, M. P.;Zlotek-Zlotkiewicz, E.;Besson, A.
p27(Kip1) （p27）在恶性转化过程中可以根据细胞环境发挥相反的作用：一方面，它通过抑制细胞核中细胞周期蛋白-细胞周期蛋白依赖性激酶（CDK）的活性而发挥肿瘤抑制作用，另一方面，它可能具有不太清楚的致癌作用。为了进一步了解p27在肿瘤发生过程中的作用，我们比较了p27（-/-）和p27（CK-）敲入两种p27小鼠模型的易感性与脲烷诱导的肿瘤发生，其中p27不能结合或抑制cyclin-CDKs。在这个k -Ras驱动的肿瘤发生模型中，与p27（-/-）相比，p27（CK-）小鼠的肿瘤数量和侵袭性都有所增加，这表明p27（CK-）和活化的Ras之间存在合作关系。在肺中，增加的肿瘤发生与p27（CK-）的细胞质定位和细支气管肺泡干细胞扩增有关。p27（CK-）与其他癌基因合作的能力并不普遍。当c-Myc用作转化剂时，p27的状态变得无关紧要，c-Myc在转化p27（+/+）、p27（-/-）和p27（CK-）细胞中同样有效。事实上，c-Myc通过Skp-Cullin-F-box (SCF)-Skp2途径诱导野生型p27的降解。相比之下，p27（CK-）水平不受c-Myc表达的影响，因为p27（CK-）无法结合cyclin E/CDK2，因此对skp2介导的降解不敏感。然而，当c-Myc存在时，p27（CK-）大部分保持核态，这解释了它在转化过程中无法与Myc合作的原因。因此，我们提出p27（CK-）蛋白需要定位在细胞质中才能发挥癌基因的作用，否则它的行为与空等位基因相似。中华肿瘤杂志（2011）30,2846-2858；doi: 10.1038 / onc.2011.9;2011年2月14日在线发布
p27(Kip1) (p27) can have opposing roles during malignant transformation depending on cellular context: on one hand it functions as a tumor suppressor by inhibiting cyclin-cyclin-dependent kinase (CDK) activity in the nucleus and on the other it may adopt an oncogenic role that is less well understood. To gain further insight into the roles played by p27 during tumorigenesis, we compared the susceptibility with urethane-induced tumorigenesis of two p27 mouse models, p27(-/-) and p27(CK-) knockin, in which p27 cannot bind or inhibit cyclin-CDKs. In this K-Ras-driven tumorigenesis model, p27(CK-) mice had an increase in both tumor number and aggressiveness compared with p27(-/-), indicating a cooperation between p27(CK-) and activated Ras. In the lung, increased tumorigenesis was associated with cytoplasmic localization of p27(CK-) and bronchiolaveolar stem cell amplification. The ability of p27(CK-) to cooperate with other oncogenes was not universal. When c-Myc was used as a transforming agent, p27 status became irrelevant and c-Myc was equally potent in transforming p27(+/+), p27(-/-) and p27(CK-) cells. In fact, c-Myc induced the degradation of wild-type p27 via the Skp-Cullin-F-box (SCF)-Skp2 pathway. In contrast, p27(CK-) levels were not affected by c-Myc expression, as p27(CK-) is insensitive to Skp2-mediated degradation because of its inability to bind cyclin E/CDK2. However, in presence of c-Myc, p27(CK-) remained mostly nuclear, providing an explanation for its inability to cooperate with Myc during transformation. Thus, we propose that the p27(CK-) protein needs to be localized in the cytoplasm in order to function as an oncogene, otherwise it just behaves similar to a null allele. Oncogene (2011) 30, 2846-2858; doi:10.1038/onc.2011.9; published online 14 February 2011