Molecular Mechanism of p73-Mediated Regulation of Hepatitis B Virus Core Promoter/Enhancer II: Implications for Hepatocarcinogenesis

Buhlmann, Sven; Raček, Tomáš; Schwarz, Alexandra; Schaefer, Stephan; Pützer, Brigitte M.

doi:10.1016/j.jmb.2008.02.021

Cited by 12 publications

(11 citation statements)

References 40 publications

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“…The above studies demonstrate the tumor‐promoting role of PLK2. However, many other studies have indicated that it is a tumor suppressor . In agreement with previous studies, PLK2 inhibition promoted cell cycle progression and cell proliferation in normal culture Saos2 cells, indicating its role as a suppressor.…”

Section: Discussionsupporting

confidence: 90%

PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells

Liao

et al. 2015

Cancer Medicine

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TAp73, a member of the p53 tumor suppressor family, can substitute for p53 function, especially in p53‐null and p53‐mutant cells. However, TAp73 enrichment and phosphorylation change its transcriptional activity. Previously, we found that the antitumor function of TAp73 was reactivated by dephosphorylation. Polo‐like kinase 2 (PLK2) plays an important role in bone development. Using a biological information database and phosphorylation prediction software, we hypothesized that PLK2 phosphorylates TAp73 and inhibits TAp73 function in osteosarcomas. Actually,we determined that PLK2 physically binds to and phosphorylates TAp73 when TAp73 protein abundance is up‐regulated by cisplatin. PLK2‐phosphorylated TAp73 at residue Ser48 within the TA domain; phosphorylation of TAp73 was abolished by mutating this residue. Moreover, PLK2 inhibition combined with cisplatin treatment in osteosarcoma Saos2 cells up‐regulated p21 and puma mRNA expression to a greater extent than cisplatin treatment alone. Inhibiting PLK2 in TAp73‐enriched Saos2 cells resulted in inhibited cell proliferation, increased apoptosis, G1 phase arrest, and decreased cell invasion. However, these changes did not occur in TAp73 knockdown Saos2 cells. In conclusion, these findings reveal a novel PLK2 function in the phosphorylation of TAp73, which prevents TAp73 activity in osteosarcoma cells. Thereby, this research provides an insight into the clinical treatment of malignant tumors overexpressing TAp73.

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Section: Discussionsupporting

confidence: 90%

PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells

Liao

et al. 2015

Cancer Medicine

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“…The synthesis of viral transcripts is controlled by four promoters and two enhancers [enhancer 1 (EnhI) and EnhII], which are regulated by various transcription factors (3). Whether these factors are recruited to the viral DNA during transcription and are involved in the transcriptional regulation in vivo is still under investigation (4,5). Chromatin immunoprecipitation (ChIP) assays indicate that the recruitment of the acetyltransferases CBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] and p300 (CBP-p300) and PCAF (p300/CBP-associated factor) to cccDNA correlates with increased HBV DNA transcription (6,7).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PP1 Phosphatase Activity by HBx: A Mechanism for the Activation of Hepatitis B Virus Transcription

et al. 2012

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The regulatory protein HBx is essential for hepatitis B virus (HBV) replication in vivo and for transcription of the episomal HBV genome. We previously reported that in infected cells HBx activates genes targeted by the transcription factor CREB [cyclic adenosine monophosphate (cAMP) response element-binding protein]. cAMP induces phosphorylation and activation of CREB, and CREB inactivation is promoted by protein phosphatase 1 (PP1), which binds to CREB through histone deacetylase 1 (HDAC1). We showed that CREB was recruited to HBV DNA. Phosphorylation induced by cAMP had a longer half-life when CREB was bound to the episomal HBV genome compared to when it was bound to the promoter of a host target gene not regulated by HBx, suggesting that the virus has developed a mechanism to favor its own transcription. This mechanism required HBx, which interacted with and inhibited PP1 to extend the half-life of CREB phosphorylation. Silencing of PP1 rescued replication of an HBx-deficient HBV genome, suggesting that HBx enhances viral transcription in part by neutralizing PP1 activity. Our results illustrate a previously unknown mechanism of HBV transcriptional activation by HBx in which HBx interferes with the inactivation of CREB by the PP1 and HDAC1 complex.

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“…Two enhancers, designated enhancer I and enhancer II, have been shown to notably up‐regulate the activities of all four viral promoters. 5–9 A number of transcription factors have been found to bind to HBV enhancers and regulate their activities, including ubiquitous transcriptional factors (e.g., nuclear factor‐1 [NF‐1], the activator protein [AP‐1], p53), liver‐enriched transcription factors (e.g., hepatocyte nuclear factor 3 [HNF3], CAAT enhancer‐binding protein [C/EBP]), and nuclear receptors in hepatocytes. 5, 6, 10 Thus, HBV enhancers are believed to be the central elements in the regulation of viral replication.…”

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confidence: 99%

Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity

Wang¹,

Qiu²,

Yan³

et al. 2012

Hepatology

236

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Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G 1 as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G 1 regulated viral replication in HBV transfected cells. We also observed that cyclin G 1 expression was up-regulated in HBV-infected patients, and cyclin G 1 levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G 1 specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53-mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells. Conclusion: miR-122 down-regulates its target cyclin G 1 , and thus interrupts the interaction between cyclin G 1 and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis. (HEPATOLOGY 2012;55:730-741)

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Molecular Mechanism of p73-Mediated Regulation of Hepatitis B Virus Core Promoter/Enhancer II: Implications for Hepatocarcinogenesis

Cited by 12 publications

References 40 publications

PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells

PLK2 phosphorylates and inhibits enriched TAp73 in human osteosarcoma cells

Inhibition of PP1 Phosphatase Activity by HBx: A Mechanism for the Activation of Hepatitis B Virus Transcription

Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity

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