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Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase.

ABSTRACT: 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 3beta-hydroxysterol Delta24-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.

SUBMITTER: Nishimura T

PROVIDER: S-EPMC2794760 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase.

Nishimura Tomohiro T Kohara Michinori M Izumi Kosuke K Kasama Yuri Y Hirata Yuichi Y Huang Ying Y Shuda Masahiro M Mukaidani Chise C Takano Takashi T Tokunaga Yuko Y Nuriya Hideko H Satoh Masaaki M Saito Makoto M Kai Chieko C Tsukiyama-Kohara Kyoko K

The Journal of biological chemistry 20091027 52

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 3beta-hydroxysterol Delta24-reductase (DHCR24) from this screen and showed that its expression reflected tumorigenicity. HCV induced the DHCR24 overexpression in human h ...[more]

PMID: 19861417

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Project description:Dietary phytosterols are cholesterol-lowering agents that interfere with the intestinal absorption of cholesterol. In the present study, we have studied their effects on cholesterol biosynthesis in human cells, particularly in the sterol-conversion pathway. For this, both Caco-2 (intestinal mucosa) and HL-60 (promyelocytic) human cell lines were incubated with [(14)C]acetate, and the incorporation of radioactivity into sterols was determined using HPLC and radioactivity detection online. Sterols containing a double bond at C-22 in the side chain (stigmasterol, brassicasterol and ergosterol) dramatically inhibited the activity of sterol Delta(24)-reductase, as indicated by the decrease in radioactivity incorporation into cholesterol and the accumulation of its precursors (mainly desmosterol). Phytosterols with the saturated side chain (beta-sitosterol and campesterol) were inactive in this regard. The inhibition of sterol (24)-reductase was confirmed in rat liver microsomes by using (14)C-labelled desmosterol as the substrate. The (22)-unsaturated phytosterols acted as competitive inhibitors of sterol (24)-reductase, with K(i) values (41.1, 42.7 and 36.8 microM for stigmasterol, brassicasterol and ergosterol respectively) similar to the estimated K(m) for desmosterol (26.3 microM). The sterol 5,22-cholestedien-3beta-ol, an unusual desmosterol isomer that lacks the alkyl groups characteristic of phytosterols, acted as a much stronger inhibitor of (24)-reductase (K(i)=3.34 microM). The usually low intracellular concentrations of the physiological substrates of (24)-reductase explains the strong inhibition of cholesterol biosynthesis that these compounds exert in cells. Given that inhibition of sterol (24)-reductase was achieved at physiologically relevant concentrations, it may represent an additional mechanism for the cholesterol-lowering action of phytosterols, and opens up the possibility of using certain (22)-unsaturated sterols as effective hypocholesterolaemic agents.

Project description:The auxin efflux transporter PIN-FORMED (PIN) family is one of the major protein families that facilitates polar auxin transport in plants. Here, we report that overexpression of OsPIN9 leads to altered plant architecture and chilling tolerance in rice. The expression profile analysis indicated that OsPIN9 was gradually suppressed by chilling stress. The shoot height and adventitious root number of OsPIN9-overexpressing (OE) plants were significantly reduced at the seedling stage. The roots of OE plants were more tolerant to N-1-naphthylphthalamic acid (NPA) treatment than WT plants, indicating the disturbance of auxin homeostasis in OE lines. The chilling tolerance assay showed that the survival rate of OE plants was markedly lower than that of wild-type (WT) plants. Consistently, more dead cells, increased electrolyte leakage, and increased malondialdehyde (MDA) content were observed in OE plants compared to those in WT plants under chilling conditions. Notably, OE plants accumulated more hydrogen peroxide (H2O2) and less superoxide anion radicals (O2-) than WT plants under chilling conditions. In contrast, catalase (CAT) and superoxide dismutase (SOD) activities in OE lines decreased significantly compared to those in WT plants at the early chilling stage, implying that the impaired chilling tolerance of transgenic plants is probably attributed to the sharp induction of H2O2 and the delayed induction of antioxidant enzyme activities at this stage. In addition, several OsRboh genes, which play a crucial role in ROS production under abiotic stress, showed an obvious increase after chilling stress in OE plants compared to that in WT plants, which probably at least in part contributes to the production of ROS under chilling stress in OE plants. Together, our results reveal that OsPIN9 plays a vital role in regulating plant architecture and, more importantly, is involved in regulating rice chilling tolerance by influencing auxin and ROS homeostasis.

Dataset Information

Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase.

Publications

Hepatitis C virus impairs p53 via persistent overexpression of 3beta-hydroxysterol Delta24-reductase.

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