Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein
Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein
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DOI：
10.1101/gad.11.16.2090
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发表时间：
1997-08-15
影响因子：
10.5
通讯作者：
Galloway, DA
中科院分区：
文献类型：
--
作者：
Funk, JO;Waga, S;Galloway, DA
p21通过不同的结构域与CDK/细胞周期蛋白复合物和PCNA结合，抑制细胞周期蛋白依赖性激酶（CDK）活性和增殖细胞核抗原（PCNA）依赖性DNA复制。人乳头瘤病毒(HPV)- 16E7癌蛋白（16E7）在体内消除了DNA损伤诱导的细胞周期阻滞，尽管p21水平很高。通过细胞裂解物和纯化蛋白，我们发现16E7可以阻止p21抑制CDK2/cyclin E活性和pna依赖性DNA复制，而非致癌的HPV-6 E7的作用则有所减弱。通过16E7与p21羧基末端与pna结合位点和第二个p21周期蛋白结合基序重叠的序列结合，实现了p21抑制功能的失活。这些数据表明，p21的羧基端同时调节CDK活性和pnas依赖的DNA复制，而一个蛋白16E7可以覆盖这种调节，从而破坏正常的细胞周期控制。
p21 inhibits cyclin-dependent kinase (CDK) activity and proliferating cell nuclear antigen (PCNA)-dependent DNA replication by binding to CDK/cyclin complexes and to PCNA through distinct domains. The human papillomavirus (HPV)-16 E7 oncoprotein (16E7) abrogated a DNA damage-induced cell cycle arrest in vivo, despite high levels of p21. Using cell lysates and purified proteins we show that 16E7 prevented p21 both from inhibiting CDK2/cyclin E activity and PCNA-dependent DNA replication, whereas the nononcogenic HPV-6 E7 had reduced effects. Inactivation of both inhibitory functions of p21 was attained through binding between 16E7 and sequences in the carboxy-terminal end of p21 that overlap with the PCNA-binding site and the second p21 cyclin-binding motif. These data imply that the carboxyl terminus of p21 simultaneously modulates both CDK activity and PCNA-dependent DNA replication and that a single protein, 16E7, can override this modulation to disrupt normal cell cycle control.