Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation

Jin, Dong-Yan; Wang, Hailin; Zhou, Yuan; Chun, Abel C.S.; Kibler, Karen V.; Hou, Yong; Kung, Hsiang‐Fu; Jeang, Kuan‐Teh

doi:10.1093/emboj/19.4.729

Cited by 121 publications

(106 citation statements)

References 85 publications

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“…Confocal Microscopy-Laser scanning confocal microscopy was performed on a Zeiss Axiophot microscope as detailed elsewhere (51,55). Dual immunofluorescent detection was achieved with primary antibodies from different species and pre-adsorbed species-specific secondary antibodies conjugated to different fluorochromes: Cy5-conjugated goat anti-mouse immunoglobulin G (Zymax) and fluorescein-conjugated goat anti-rabbit immunoglobulin G (Zymax).…”

Section: Methodsmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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The anaphase-promoting complex activated by CDC20 and CDH1 is a major ubiquitination system that controls the destruction of cell cycle regulators. Exactly how ubiquitination is regulated in time and space is incompletely understood. Here we report on the cell cycle-dependent localization of CDH1 and its regulation by phosphorylation. CDH1 localizes dynamically to the nucleus during interphase and to the centrosome during metaphase and anaphase. The nuclear accumulation of CDH1 correlates with a reduction in the steady-state amount of cyclin A, but not of cyclin E. A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus. On the other hand, abolition of the cyclin-binding ability of CDH1 has no influence on its nuclear localization. Taken together, our findings document the phosphorylation-dependent localization of CDH1 in vertebrate cells.The timely and orderly progression of eukaryotic cell division cycle is precisely controlled through ubiquitination-induced proteolysis. The anaphase-promoting complex (APC) 1 functions as a major ubiquitin ligase in the cell, and it governs anaphase onset, mitotic exit, and G 1 events (1-4). APC is a large complex of multiple subunits. It catalyzes the formation of polyubiquitin chains on cyclins and other cell cycle regulators and thereby targets them for degradation by proteosome. The components of APC are highly conserved in organisms ranging from yeast to humans. The rise and fall of APC activity is stringently regulated in a cell cycle-dependent manner. It plateaus at the transition from metaphase to anaphase, remains high throughout G 1 , and drops in S/G 2 until early mitosis (5). One important mechanism for the regulation of APC is through phosphorylation of its subunits (6 -9). In addition, CDC20 and CDH1 can act as activators and specificity factors of APC (10 -15).CDC20 and CDH1 are WD40 repeat proteins that associate transiently with and activate APC in a substrate-specific fashion. Many substrate proteins targeted by the CDC20-and CDH1-activated APC share a sequence motif known as destruction box (5, 16). Another motif termed the KEN box is recognized by CDH1-activated APC and has been found in substrates including CDC20, NEK2, HSL1, mitotic cyclins, and securin (17)(18)(19)(20). In addition, a distinct recognition domain called the A box has been shown to be required for CDH1-dependent ubiquitination and degradation of the Aurora-A kinase (21). Exactly how CDC20 and CDH1 activate APC remains to be fully understood. Existing evidence suggests that they mediate the temporal and spatial activation of APC throu...

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Section: Methodsmentioning

confidence: 99%

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Zhou

Ching

Chun

et al. 2003

Journal of Biological Chemistry

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“…Apart from acting as the basic building block of viral nucleocapsid, it also interacts with a variety of cellular factors, interfering with their normal functions (Lai and Ware, 2000;Ray and Ray, 2001). For instance, HCV core protein has been shown to target several cellular transcription factors such as hnRNP K (Hsieh et al, 1998), LZIP (Jin et al, 2000), 14-3-3 (Aoki et al, 2000), p21/WAF1 , and RNA helicase CAPRf (You et al, 1999), resulting in the alterations in the responsive transcription regulatory activities. Moreover, HCV core protein is able to cooperate with ras oncogene in the transformation of rodent fibroblasts under certain conditions (Chang et al, 1998), to influence host cell growth and proliferation through different mechanisms (Aoki et al, 2000;Cho et al, 2001;Erhardt et al, 2002), to promote immortalization of primary human hepatocytes (Ray et al, 2000), and to cause HCC formation at the late stage of transgenic mice (Moriya et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

Kao

Chen

Chen³

et al. 2004

Oncogene

115

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Oncogenic virus proteins often target to tumor suppressor p53 during virus life cycle. In the case of hepatitis C virus (HCV) core protein, it has been shown to affect p53-dependent transcription. Here, we further characterized the in vitro and in vivo interactions between HCV core protein and p53 and showed that these two proteins colocalized in subnuclear granular structures and the perinuclear area. By use of a reporter assay, we observed that while low level of HCV core protein enhanced the transactivational activity of p53, high level of HCV core protein inhibited this activity. In both cases, however, HCV core protein increased the p53 DNA-binding affinity in gel retardation analyses, likely due to the hyperacetylation of p53 Lys 373 and Lys 382 residues. Additionally, HCV core protein, depending on its expression level, had differential effects on the Ser 15 phosphorylation of p53. Moreover, HCV core protein could rescue p53-mediated suppressive effects on both RNA polymerase I and III transcriptions. Collectively, our results indicate that HCV core protein targets to p53 pathway via at least three means: physical interaction, modulation of p53 gene regulatory activity and post-translational modification. This feature of HCV core protein, may potentially contribute to the HCV-associated pathogenesis.

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“…HCV core has been described as being associated with lymphotoxin-b receptor, TNF-receptor 1, apolipoprotein AII, hnRNP and a bZIP transcription factor (Barba et al, 1997;Chen et al, 1997;Hsieh et al, 1998;Sabile et al, 1999). Evidence exists that HCV core may have an e ect upon cell transformation (Jin et al, 2000) and apoptosis (Marusawa et al, 1999;Ray et al, 1996Ray et al, , 1998Ruggieri et al, 1997); however, the biological consequences of core ectopic expression depend on the levels of expression achieved, the cell type utilized and the cellular environment (Honda et al, 2000;Zhu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

et al. 2001

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Hepatitis C virus (HCV) is a major etiological agent of chronic liver disease and hepatocellular carcinoma (HCC). We demonstrate herewith that HCV core proteins encoded by sequences isolated from HCC tumor tissues, but not those derived from their non-tumor counterparts in the same liver, co-localise in vitro and in vivo and co-immunoprecipitate with PKR in hepatocytic Huh7 cells. We show that this association in fact augments the autophosphorylation of PKR and the phosphorylation of the translation initiation factor eIF2a, which are two markers of PKR activity. The present study therefore identi®es a novel model of viruscell interactions whereby a viral protein, the HCV core, activates PKR activity. Oncogene (2001) 20, 5836 ± 5845.

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Hepatitis C virus core protein-induced loss of LZIP function correlates with cellular transformation

Cited by 121 publications

References 85 publications

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Nuclear Localization of the Cell Cycle Regulator CDH1 and Its Regulation by Phosphorylation

Modulation of p53 transcription regulatory activity and post-translational modification by hepatitis C virus core protein

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

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