Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase
Hepatitis C Virus Impairs p53 via Persistent Overexpression of 3β-Hydroxysterol Δ24-Reductase
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DOI：
10.1074/jbc.m109.043232
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Tsukiyama-Kohara, Kyoko
中科院分区：
文献类型：
--
作者：
Nishimura, Tomohiro;Kohara, Michinori;Tsukiyama-Kohara, Kyoko
丙型肝炎病毒（HCV）持续感染可诱导肝细胞致瘤性。为了深入了解这一过程的机制，我们在全基因组范围内产生了针对HCV表达的人肝母细胞瘤衍生细胞系RzM6-LC的单克隆抗体，显示出增强的致瘤性。我们从该筛选中鉴定了3 β-羟基甾醇Δ 24-还原酶（DHCR 24），并表明其表达反映了致瘤性。HCV诱导DHCR 24在人肝细胞中过表达。异位或HCV诱导的DHCR24过表达导致对氧化应激诱导的细胞凋亡的抵抗，并抑制p53活性。DHCR24在这些细胞中的过表达增加了细胞质中p53和MDM2（也称为HDM2）（一种p53特异性E3泛素连接酶）之间的相互作用。持续DHCR24过表达并不改变p53的磷酸化状态，但导致过氧化氢处理后细胞核中p53赖氨酸残基373和382处的乙酰化降低。综上所述，这些结果表明，DHCR 24响应于HCV感染而升高，并通过刺激MDM 2-p53复合物在细胞质中的积累和通过抑制细胞核中p53的乙酰化来抑制p53应激反应。
Persistent infection with hepatitis C virus (HCV) induces tumorigenicity in hepatocytes. To gain insight into the mechanisms underlying this process, we generated monoclonal antibodies on a genome-wide scale against an HCV-expressing human hepatoblastoma-derived cell line, RzM6-LC, showing augmented tumorigenicity. We identified 3 beta-hydroxysterol Delta 24-reductase (DHCR24) from this screen and showed that its expression reflected tumorigenicity. HCV induced the DHCR24 overexpression in human hepatocytes. Ectopic or HCV-induced DHCR24 overexpression resulted in resistance to oxidative stress-induced apoptosis and suppressed p53 activity. DHCR24 overexpression in these cells paralleled the increased interaction between p53 and MDM2 (also known as HDM2), a p53-specific E3 ubiquitin ligase, in the cytoplasm. Persistent DHCR24 overexpression did not alter the phosphorylation status of p53 but resulted in decreased acetylation of p53 at lysine residues 373 and 382 in the nucleus after treatment with hydrogen peroxide. Taken together, these results suggest that DHCR24 is elevated in response to HCV infection and inhibits the p53 stress response by stimulating the accumulation of the MDM2-p53 complex in the cytoplasm and by inhibiting the acetylation of p53 in the nucleus.