HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53

Klein, Andreas; Guhl, Eva; Tzeng, Yin-Jeh; Fuhrhop, Jutta; Levrero, Massimo; Graessmann, M.; Graessmann, A.

doi:10.1038/sj.onc.1206539

Cited by 40 publications

(35 citation statements)

References 41 publications

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“…Previous studies reported that HBx disturbed multiple check-points in primary mouse liver cells, established cell lines, and HBx transgenic mice (6)(7)(8)(9)(10). Here, our study showed that HBx also induced cell cycle arrest at G2/M phase.…”

Section: Discussionsupporting

confidence: 60%

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Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Cheng¹,

Li²,

Yang³

et al. 2009

Oncol Rep

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Abstract. Hepatitis B virus X protein (HBx) is a multifunctional regulatory protein that is known to be involved in viral proliferation, transcriptional activation and cell growth control. However, the actual role of HBx in cell growth control remains controversial. In this study, the impact of HBx on cell growth in vitro and in vivo was further investigated. HBx was able to inhibit the growth of hepatocellular carcinoma (HCC) cells and induce G2/M arrest in vitro. Moreover, unlike many other G2/M arrest mechanisms, HBx did not inhibit cyclin B1-CDK1 kinase activity, but it persistently activated the cyclin B1-CDK1 kinase. In vivo, HBx inhibited tumor cell growth and induced apoptosis as well as inhibited the growth of vascular endothelial cells. In conclusion, HBx induced G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase, and negatively regulated cell growth in vitro and in vivo.

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Section: Discussionsupporting

confidence: 60%

“…The effects of HBx on cell cycle progression are potentially more complicated. Some studies found that HBx stimulated cell cycle progression, accelerating transit through checkpoint controls at G0/G1 (7)(8)(9). Other reports showed that HBx could block G0/G1 and G1/S transit or had no effect on cell cycle profiles (6,10).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Cheng¹,

Li²,

Yang³

et al. 2009

Oncol Rep

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“…Recent data suggest that HBx-mediated cyclin D1 up-regulation in mammary gland cells can induce tumors as well despite the differences between hepatocyte and mammary gland cells (18). In this report, we show that HBx up-regulates cyclin D1 in Chang liver cells (immortalized hepatocyte cell line) and HepG2.2.15 cells (HBV-producing cell line derived from hepatoblastoma cell line).…”

Section: Discussionmentioning

confidence: 60%

“…Previous studies have suggested a link between HBx and cyclin D1 where cyclin D1 is shown to be up-regulated by HBx (18). Overexpression of cyclin D1 is involved in tumor development and growth (19) as well as in HCC.…”

Section: Hepatitis B Virus (Hbv)mentioning

confidence: 99%

Up-regulation of Cyclin D1 by HBx Is Mediated by NF-κB2/BCL3 Complex through κB Site of Cyclin D1 Promoter

Park¹,

Chung²,

Kang³

et al. 2006

J. Biol. Chem.

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Cyclin D1 is frequently overexpressed in hepatocellular carcinoma (HCC) exhibiting increased malignant phenotypes. It has also been known that the hepatitis Bx (HBx) protein is strongly associated with HCC development and progression. Although overexpression of both proteins is related to HCC, the relationship between the two has not been well studied. Here we show that HBx up-regulates cyclin D1 and that this process is mediated by the NF-B2(p52)/BCL-3 complex. Our experiments indicate that HBx up-regulates BCL-3 in the mRNA level, which subsequently results in the up-regulation of the NF-B2(p52)/ BCL-3 complex in the nucleus. Moreover, impaired HBx-mediated BCL-3 up-regulation by small interfering RNA for BCL-3 reduced HBx-mediated cyclin D1 up-regulation. Down-regulation of the HBx protein level by p53 also reduced HBx-mediated cyclin D1 up-regulation. From these results, we conclude that the up-regulation of cyclin D1 by HBx is mediated by the up-regulation of NF-B2(p52)/BCL-3 in the nucleus. This HBx-mediated-cyclin D1 up-regulation might play an important role in the HBx-mediated HCC development and progression.

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“…48,79 HBx increases the rate and level of activation of CDK2, where the rate is associated with cyclins E and A, and the level with cyclin B. 80 HBx also causes cyclin D1 overexpression, 81 the Rb gene is a key player in the G1/S checkpoint system, and HBxAg transactivates the Rb promoter. 48 Increased levels of phosphorylated Rb result in the release of E2F from Rb and cell-cycle progression.…”

Section: Ink4dmentioning

confidence: 99%

Molecular Pathogenesis of Hepatitis-B-virus-associated Hepatocellular Carcinoma

Park¹,

Song²,

Chung³

2007

Gut Liver

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Hepatocellular carcinoma (HCC) is one of the most frequent and malignant diseases worldwide. Epidemiological studies have clearly demonstrated that chronic hepatitis B virus (HBV) infection is a major etiological factor in the development of HCC. The pathogenesis of HBV-associated HCC has been studied extensively, and the molecular changes associated with malignant transformation have been identified. The predominant carcinogenic mechanisms of HBV-associated HCC are chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation. An important role is also played by the integration of HBV DNA into host cellular DNA, which disrupts or promotes the expression of cellular genes that are important in cell growth and differentiation. Especially, HBx protein is a transactivating protein that promotes cell growth, survival, and the development of HCC. Continued investigation of the mechanisms underlying hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in the liver. Prevention of HBV infections and effective treatments for chronic hepatitis B are still needed for the global control of HBV-associated HCC. This review summarizes the current knowledge on the mechanisms involved in HBV-associated hepatocarcinogenesis. (Gut and Liver 2007;1: 101-117)

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HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53

Cited by 40 publications

References 41 publications

Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Up-regulation of Cyclin D1 by HBx Is Mediated by NF-κB2/BCL3 Complex through κB Site of Cyclin D1 Promoter

Molecular Pathogenesis of Hepatitis-B-virus-associated Hepatocellular Carcinoma

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