HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription.
HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription.
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DOI：
10.1016/j.jhep.2013.01.014
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发表时间：
2013-06
影响因子：
25.7
通讯作者：
Lok, Anna S. F.
中科院分区：
文献类型：
--
作者：
Huang, Yuehua;Tai, Andrew W.;Tong, Shuping;Lok, Anna S. F.
Hepatitis B virus (HBV) core promoter (CP) mutations have been associated with an increased risk of hepatocellular carcinoma (HCC) in clinical studies. We previously reported that a combination of CP mutations seen in HCC patients, expressed in HBx gene, increased SKP2 (S-phase kinase-associated protein 2) expression thereby promoting cellular proliferation. Here, we investigate the possible mechanisms by which CP mutations up-regulate SKP2. We used immunoblotting and ATPlite assay to validate the effect of CP mutations in full length HBV genome on cell cycle regulator levels and cell proliferation. Activation of SKP2 mRNA was assessed by quantitative real time PCR in primary human hepatocytes and HCC cell lines. Effect of CP mutations on SKP2 promoter activity was determined by luciferase assay. Target regulation of E2F1 on SKP2 was analyzed by siRNAs. CP mutations in full length HBV genome up-regulated SKP2 expression thereby down-regulating cell cycle inhibitors and accelerating cellular proliferation. CP mutations enhanced SKP2 promoter activity but had no effect on SKP2 protein stability. Mapping of the SKP2 promoter identified a region necessary for activation by CP mutations that contain an E2F1 response element. Knocking down E2F1 reduced the effects of CP mutations on SKP2 and cellular proliferation. Effect of CP mutations on E2F1 might be mediated through hyperphosphorylation of RB. HBV CP mutations enhance SKP2 transcription by activating the E2F1 transcription factor and in turn down-regulate cell cycle inhibitors thus providing a potential mechanism for an association between CP mutations and HCC.
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影响因子：
11.8
作者：
Nakayama, K;Nagahama, H;Nakayama, KI
通讯作者：
Nakayama, KI
DOI：
10.1093/jnci/djn243
发表时间：
2008-08-20
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Yang HI;Yeh SH;Chen PJ;Iloeje UH;Jen CL;Su J;Wang LY;Lu SN;You SL;Chen DS;Liaw YF;Chen CJ;REVEAL-HBV Study Group
通讯作者：
REVEAL-HBV Study Group
影响因子：
8
作者：
Conner, EA;Lemmer, ER;Thorgeirsson, SS
通讯作者：
Thorgeirsson, SS
DOI：
10.1093/jnci/djp180
发表时间：
2009-08-05
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Liu S;Zhang H;Gu C;Yin J;He Y;Xie J;Cao G
通讯作者：
Cao G
影响因子：
5.4
作者：
Gearhart, Tricia L.;Bouchard, Michael J.
通讯作者：
Bouchard, Michael J.