CIP2A facilitates the G1/S cell cycle transition via B-Myb in human papillomavirus 16 oncoprotein E6-expressing cells.
CIP2A facilitates the G1/S cell cycle transition via B-Myb in human papillomavirus 16 oncoprotein E6-expressing cells.
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CIP2A 通过 B-Myb 在人乳头瘤病毒 16 癌蛋白 E6 表达细胞中促进 G1/S 细胞周期转变
DOI：
10.1111/jcmm.13693
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发表时间：
2018-09
影响因子：
5.3
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Tian Y;Chen H;Qiao L;Zhang W;Zheng J;Zhao W;Chen JJ;Zhang W
高危型人乳头瘤病毒（HR-HPV，包括HPV-16、HPV-18、HPV-31）感染在宫颈癌的发生中起着重要的病因作用。HR-HPV的转化特性主要存在于病毒癌蛋白E6和E7中。E6蛋白降解肿瘤抑制因子p53并消除细胞周期检查点。蛋白磷酸酶2A癌抑制因子（CIP 2A）是一种与多种人类恶性肿瘤的发生有关的癌蛋白。我们以前的数据显示，CIP 2A在宫颈癌中过表达。然而，HPV-16 E6对CIP 2A的调控仍有待阐明。在这项研究中，我们证明HPV-16 E6以p53降解依赖性方式显著上调CIP 2A mRNA和蛋白表达。通过siRNA敲低CIP 2A抑制活力和DNA合成，并导致表达16 E6的细胞的G1细胞周期停滞。CIP 2A的敲低导致细胞周期蛋白依赖性激酶1（Cdk 1）和Cdk 2的表达显著降低。虽然CIP 2A已被报道通过抑制PP 2A介导的c-Myc去磷酸化来稳定c-Myc，但我们已经提出了CIP 2A对Cdk 1和Cdk 2的调节依赖于转录因子B-MyB而不是c-Myc的证据。总之，我们的研究揭示了CIP 2A在消除HPV-16 E6表达细胞中的G1检查点中的作用，并有助于理解HPV诱导的肿瘤发生的分子基础。
Infection with high‐risk human papillomaviruses (HR‐HPVs, including HPV‐16, HPV‐18, HPV‐31) plays a central aetiologic role in the development of cervical carcinoma. The transforming properties of HR‐HPVs mainly reside in viral oncoproteins E6 and E7. E6 protein degrades the tumour suppressor p53 and abrogates cell cycle checkpoints. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is involved in the carcinogenesis of many human malignancies. Our previous data showed that CIP2A was overexpressed in cervical cancer. However, the regulation of CIP2A by HPV‐16E6 remains to be elucidated. In this study, we demonstrated that HPV‐16E6 significantly up‐regulated CIP2A mRNA and protein expression in a p53‐degradation‐dependent manner. Knockdown of CIP2A by siRNA inhibited viability and DNA synthesis and caused G1 cell cycle arrest of 16E6‐expressing cells. Knockdown of CIP2A resulted in a significant reduction in the expression of cyclin‐dependent kinase 1 (Cdk1) and Cdk2. Although CIP2A has been reported to stabilize c‐Myc by inhibiting PP2A‐mediated dephosphorylation of c‐Myc, we have presented evidence that the regulation of Cdk1 and Cdk2 by CIP2A is dependent on transcription factor B‐Myb rather than c‐Myc. Taken together, our study reveals the role of CIP2A in abrogating the G1 checkpoint in HPV‐16E6‐expressing cells and helps in understanding the molecular basis of HPV‐induced oncogenesis.
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