HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

Kim, S.; Park, S. Y.; He, Yong; Famulski, Jakub K.; Chae, Sunyoung; Lee, J. H.; Kang, Chang‐Mo; Saya, Hideyuki; Chan, Gordon K.; Cho, Hyeseong

doi:10.1038/sj.onc.1210998

Cited by 60 publications

(42 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 HBx has also recently been proposed to induce lagging chromosomes by binding to BubR1 to disrupt the mitotic checkpoint complex, which keeps the anaphasepromoting complex inactive during mitosis, thereby leading cells to escape mitotic arrest when exposed to spindle toxins. 23 However, we failed to obtain evidence that HBx deregulates the spindle assembly checkpoint (Fig. 2).…”

Section: Discussionmentioning

confidence: 78%

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Lluesma¹,

Schaeffer²,

Robert³

et al. 2008

Hepatology

View full text Add to dashboard Cite

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC), but its role in the transformation process remains unclear. HBV encodes a small protein, known as HBx, which is required for infection and has been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging chromosomes during mitosis, which in turn leads to formation of aberrant mitotic spindles and multinucleated cells. These effects require the binding of HBx to UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell cycle regulation, and are unexpectedly attributable to HBx interfering with S-phase progression and not directly with mitotic events. HBx also affects S-phase and induces lagging chromosomes when expressed from its natural viral context and, consequently, exhibits deleterious activities in dividing, but not quiescent, hepatoma cells. Conclusion: In addition to its reported role in promoting HBV replication, the binding of HBx to DDB1 may induce genetic instability in regenerating hepatocytes and thereby contribute to HCC development, thus making this HBV-host protein interaction an attractive target for new therapeutic intervention. (HEPATOLOGY 2008;48:1467-1476.)H epatocellular carcinoma (HCC) is the fifth most frequent cancer in humans, accounting for nearly 1 million deaths annually, and is mainly the consequence of chronic hepatitis B virus (HBV) infection. 1 HBV encodes a small regulatory protein, termed HBx, which is essential for virus replication in vivo and is expressed during chronic infection. 2 HBx has also been implicated in hepatocarcinogenesis. HBx is conserved among all mammalian hepatitis viruses that cause liver cancer in their hosts, whereas no counterpart exists in the non-oncogenic avian hepatitis viruses. Evidence derived from tumor sample analysis, cell culture, and transgenic animal studies collectively supports a role for HBx in HCC development. 3,4 However, the mechanism by which HBx may contribute to hepatocyte transformation remains obscure.In cell culture, HBx exhibits many activities, including an ability to stimulate HBV replication and to interfere with cell cycle progression, and it is believed to do so through interaction with cellular proteins. 2 Among these is UV-damaged DNA binding protein 1 (DDB1), a highly conserved 127-kDa protein that is also targeted by other viral regulatory proteins (see Discussion) and that functions as a subunit of an E3 ubiquitin ligase complex, in which it serves an adapter function to select specific targets for ubiquitin-dependent proteolysis. 5 Previous work demonstrated that HBx stimulates HBV genome replication by binding to DDB1 in the nuclear compartment of cells. 6 A nuclear interaction with DDB1 is also required for HBx to interfere with cell viability. 7 A similar DDB1-binding dependent cytotoxic activity has been re-

show abstract

Section: Discussionmentioning

confidence: 78%

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Lluesma¹,

Schaeffer²,

Robert³

et al. 2008

Hepatology

View full text Add to dashboard Cite

show abstract

“…Alternatively, HBx protein itself may increase 3These authors contributed equally to this work. the genetic instability in host cells, possibly by amplifying the centrosome numbers (Forgues et al, 2003;Kim et al, 2008;Yun et al, 2004). In addition, HBx binds HBXIP, which plays an important role in centrosome duplication and microtubule stability in mitosis (Wen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

Kim

Lee

et al. 2015

Journal of General Virology

View full text Add to dashboard Cite

Genetic instability is intimately associated with tumour development. In particular, liver cancers associated with hepatitis B virus (HBV) exhibit high genetic instability; however, our understanding of the underlying molecular mechanisms remains limited. In this study, we found that c-H2AX, a marker of DNA double-strand breaks (DSBs), and the levels of phospho-Chk2 (p-Chk2, the activated form) were significantly elevated in HBV-associated hepatocellular carcinomas and neighbouring regenerating nodules. Likewise, introduction of the pHBV or pMyc-HBx plasmids into cells induced accumulation of c-H2AX foci and increased the p-Chk2 level. In these cells, inhibitory phosphorylation of Cdc25C phosphatase (Ser 216 ) and CDK1(Tyr 15 ) was elevated; consequently, cell-cycle progression was delayed at G 2 /M phase, suggesting that activation of the ATM-Chk2 pathway by the HBV X protein (HBx) induces cell-cycle delay. Accordingly, inhibition of ataxia telangiectasia mutated (ATM) by caffeine or siRNA abolished the increase in the p-Chk2 level and restored the delayed CDK1 kinase activity in ChangX cells. We also found that cytoplasmic HBx, but not nuclear HBx, induced reactive oxygen species (ROS) production and led to the accumulation of c-H2AX foci and the increased p-Chk2 level. Together, these data indicate that HBx-induced ROS accumulation induces DNA damage that activates the ATM-Chk2 pathway. Our findings provide insight into the mechanisms of HBV pathogenesis.

show abstract

“…Some reported targets of these viral proteins are BUB1, BUBR1, MAD1 and MAD2 (22,(54)(55)(56). To our knowledge, there have been no studies evaluating BUBR1 expression in OSCC associated with HPV infection by IHC.…”

Section: Discussionmentioning

confidence: 99%

“…Individuals with missense or truncating mutations in the BUBR1 gene are predisposed to ONCOLOGY REPORTS 23: 1027-1036, 2010 BUBR1 expression in benign oral lesions and squamous cell carcinomas: Correlation with human papillomavirus the development of childhood cancer including rhabdomyosarcoma, Wilms tumor, and leukemia (21). However, BUBR1 mRNA and/or protein overexpression has been found to be associated with tumor recurrence and progression of renal and bladder cancer (22,23), and was also observed in malignant salivary gland tumors and in breast and gastric cancer (24)(25)(26). Since HPV has been cited as a risk factor of oral carcinogenesis, and since some studies have shown the association between viral proteins and the BUBR1 (22,27), the aim of the present study was to evaluate the expression of BUBR1 immunoperoxidase in non-malignant oral lesions and in OSCC with and without metastasis associated with HPV infection.…”

Section: Introductionmentioning

confidence: 99%

“…However, BUBR1 mRNA and/or protein overexpression has been found to be associated with tumor recurrence and progression of renal and bladder cancer (22,23), and was also observed in malignant salivary gland tumors and in breast and gastric cancer (24)(25)(26). Since HPV has been cited as a risk factor of oral carcinogenesis, and since some studies have shown the association between viral proteins and the BUBR1 (22,27), the aim of the present study was to evaluate the expression of BUBR1 immunoperoxidase in non-malignant oral lesions and in OSCC with and without metastasis associated with HPV infection. An additional objective was to compare quantitative analyses of BUBR1 performed with a computer-assisted system to quantification by a pathologist.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

BUBR1 expression in benign oral lesions and squamous cell carcinomas: Correlation with human papillomavirus

Soares¹

2010

Oncol Rep

View full text Add to dashboard Cite

Abstract. Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Only in Brazil, the estimate is for 14,160 new cases in 2009. HPV is associated with increasing risk of oral cancer, but its role in carcinogenesis is still controversial. BUBR1, an important protein in the mitotic spindle assembly checkpoint (SAC), has been associated with some virus-encoded proteins and cancer. The aim of the present study was to evaluate the expression of BUBR1 in non-malignant oral lesions and OSCC with and without metastasis associated with HPV infection. We performed immunohistochemistry for BUBR1 in 70 OSCC biopsies divided into three groups (in situ tumors, invasive tumors without metastasis and invasive tumors with metastasis) with their respective lymph nodes from samples with metastasis and in 16 non-malignant oral lesions. PCR was performed in order to detect HPV DNA. Significantly higher BUBR1 expression associated with shorter survival (p=0.0479) was observed in malignant lesions. There was also a significant correlation (r=1.000) with BUBR1 expression in lesions with metastasis and their lymph nodes. Ninety percent of OSCC and 100% of benign lesions were HPV positive. HPV16 and HVP18 were present in 13 and 24% of HPV-positive OSCC samples, respectively. HPV was more prevalent (76%) in samples with a high BUBR1 expression and the absence of viral DNA had no influence on BUBR1 expression. These findings suggest that HPV could be associated with overexpression of BUBR1 in OSCC, but not in benign oral lesions.

show abstract

HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

Cited by 60 publications

References 29 publications

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

Hepatitis B virus X protein activates the ATM–Chk2 pathway and delays cell cycle progression

BUBR1 expression in benign oral lesions and squamous cell carcinomas: Correlation with human papillomavirus

Contact Info

Product

Resources

About