The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21(Cip1)-mediated inhibition of cdk2
The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21(Cip1)-mediated inhibition of cdk2
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DOI：
10.1101/gad.11.16.2101
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发表时间：
1997-08-15
影响因子：
10.5
通讯作者：
Munger, K
中科院分区：
文献类型：
--
作者：
Jones, DL;Alani, RM;Munger, K
高危型人乳头瘤病毒(HPV)与大多数人类宫颈癌的病因学相关。这些HPV编码两种病毒癌蛋白EB和E7，这两种蛋白在宫颈癌中持续表达。这些病毒癌蛋白在生产性感染期间的功能是确保病毒在正常情况下退出细胞分裂周期并致力于终末分化的细胞中复制。研究表明，E7癌蛋白的表达可导致多种负向生长调节信号的消失，包括P53介导的G(1)生长停滞、转化生长因子β介导的生长抑制以及基底层以上角质形成细胞的静止。在这里，我们描述了一种新的机制，通过它E7可以解开细胞的增殖和分化。与正常分化的角质形成细胞相比，表达HPV-16E7的角质形成细胞表现出细胞分化延迟和CDK2激酶活性升高，尽管p21(Cip1)水平较高，p21(Cip1)与CDK2相关。我们发现，HPVE7蛋白可以与p21(Cip1)相互作用，并阻断p21(Cip1)介导的抑制细胞周期蛋白A和E相关的激酶活性。基于这些发现，我们认为，HPV E7癌蛋白在角质形成细胞分化过程中克服p21(Cip1)介导的CDK2活性抑制的能力有助于E7在分化的角质形成细胞中允许细胞DNA合成。
The high risk human papillomaviruses (HPVs) are associated etiologically with the majority of human cervical carcinomas. These HPVs encode two viral oncoproteins, Eb and E7, which are expressed consistently in cervical cancers. The function of these viral oncoproteins during a productive infection is to ensure viral replication in cells that have normally withdrawn from the cell division cycle and are committed to terminal differentiation. Expression of the E7 oncoprotein has been shown to lead to the abrogation of various negative growth regulatory signals, including a p53-mediated G(1) growth arrest, TGF beta-mediated growth inhibition, and quiescence of suprabasal keratinocytes. Here we describe a novel mechanism by which E7 can uncouple cellular proliferation and differentiation. In contrast to normal, differentiating keratinocytes, HPV-16 E7-expressing keratinocytes show delayed cellular differentiation and elevated cdk2 kinase activity despite high levels of p21(Cip1) and association of p21(Cip1) With cdk2. We show that the HPV E7 protein can interact with p21(Cip1) and abrogate p21(Cip1)-mediated inhibition of cyclin A and E-associated kinase activities. Based on these findings, we propose that this capacity of the HPV E7 oncoprotein to overcome p21(Cip1)-mediated inhibition of cdk2 activity during keratinocyte differentiation contributes to the ability of E7 to allow for cellular DNA synthesis in differentiated keratinocytes.