The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner
The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner
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DOI：
10.1038/sj.onc.1210541
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发表时间：
2007-11-15
期刊：
影响因子：
8
通讯作者：
McCance, D. J.
中科院分区：
文献类型：
--
作者：
Charette, S. T.;McCance, D. J.
细胞周期蛋白依赖性激酶抑制剂p27（kip 1）（p27）最近被认为是细胞运动的正调节剂，并且当定位于细胞质时，是几种形式的癌症中预后不良的标志物。细胞质p27通过结合并抑制小G T β和细胞骨架组织者RhoA的活化，从而放松细胞底物的抓持并增强运动，从而对迁移发挥作用。使用DNA损伤作为p27核输入信号，我们发现，E7癌蛋白从人乳头瘤病毒16型（HPV-16），宫颈癌的病原体，增强细胞质中的保留p27和迁移的人包皮角质形成细胞（HFKs）在磷酸肌醇-3激酶（PI 3 K）/Akt依赖的方式使用标准的伤口检测。E7表达的HFKs中迁移增加与Akt调节的RhoA活性下调相关，在给定p27核输入信号的条件下，通过p27结合（即DNA损伤）。在这些条件下，下游RhoA效应器ROCK的抑制增强对照细胞迁移，而相对不影响E7表达细胞，进一步暗示E7对RhoA的抑制作用正调节迁移。我们认为，HPV-16的E7蛋白可以调节p27的细胞质定位，并可能反过来通过PI 3 K/Akt途径调节肿瘤转移/侵袭性。
Cyclin-dependent kinase inhibitor p27(kip1) (p27) has recently been implicated as a positive regulator of cellular motility and is a marker of poor prognosis in several forms of cancer when localized to the cytoplasm. Cytoplasmic p27 exerts its effect on migration by binding to and inhibiting the activation of the small GTPase and cytoskeletal organizer RhoA, consequentially loosening cell substrate grip and enhancing movement. Using DNA damage as a p27 nuclear import signal, we found that the E7 oncoprotein from human papillomavirus type 16 (HPV-16), the etiological agent of cervical cancer, enhanced both the cytoplasmic retention of p27 and the migration of human foreskin keratinocytes (HFKs) in a phosphoinositide-3 kinase (PI3K)/Akt-dependent manner using a standard wound assay. Increased migration in E7-expressing HFKs correlated with an Akt-regulated downregulation of RhoA activity through p27 binding under conditions where a p27 nuclear import signal is given (that is, DNA damage). Under these conditions, inhibition of the downstream RhoA effector ROCK enhanced control cell migration, whereas relatively unaffecting E7-expressing cells, further implicating that the inhibitory effect of E7 on RhoA positively regulates migration. We believe that the E7 protein from HPV-16 can modulate the cytoplasmic localization of p27 and may in turn regulate tumor metastasis/aggressiveness through the PI3K/Akt pathway.