p53 in malignant and benign liver lesions

Schaff, Z.; Sarosi, Ildiko; Hsia, Chu Chieh; Kiss, András; Tabor, Edward

doi:10.1016/0959-8049(95)00380-2

Cited by 17 publications

(8 citation statements)

References 21 publications

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“…This finding is in agreement with other studies and suggests that p53 may have a significant role in HCC hepatocarcinogenesis (Choi et al, 1993;Schaff et al, 1995;Moudgil et al, 2013). However, mutational analysis will be required to confirm this suggestion, as a build-up of p53 protein as detected by immunohistochemistry is not necessarily indicative of mutation (Kennedy et al, 1994).…”

Section: Discussionsupporting

confidence: 81%

Tissue Microarray Immunohistochemical Profiles of p53 and pRB in Hepatocellular Carcinoma and Hepatoblastoma

Azlin¹,

Looi²,

Cheah³

2014

Asian Pacific Journal of Cancer Prevention

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Section: Discussionsupporting

confidence: 81%

Tissue Microarray Immunohistochemical Profiles of p53 and pRB in Hepatocellular Carcinoma and Hepatoblastoma

Azlin¹,

Looi²,

Cheah³

2014

Asian Pacific Journal of Cancer Prevention

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“…Also, in most investigations in which p53 was detected in HCC, the nucleus has been the subcellular location of this protein. [80][81][82] Collectively these data suggest that functional inactivation of p53 by HBx may occur early during hepatocarcinogenesis and the predominant nuclear localization of p53 in HCC may be a late phenomenon that reflects accumulation of mutant and inactive p53.…”

Section: Interaction Between Hbx and P53mentioning

confidence: 88%

Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen‐activated protein kinase and JAK/STAT pathways

Arbuthnot¹,

Capovilla²,

Kew

2000

J of Gastro and Hepatol

180

121

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The genome of HBV, as with other hepadnaviruses, is composed of circular, partly double-stranded DNA 5,6 ( Fig. 1).The long (minus) strand is approximately 3200 bases in length, and contains four open reading frames (ORF) that encode viral proteins and the cis-elements that are required for regulation of HBV gene expression and replication. 7 A plus strand of variable length maintains the circular structure of the genome by cohesive hybridization that straddles the 5¢ and 3¢ ends of the minus strand. Each ORF overlaps at least one other, and together they cover the entire genome. Thus, the cis-elements are included within the protein coding regions. This compact arrangement results in a highly economical utilization of the small genome. Abstract Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.

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“…Moreover, cytoplasmic sequestration of p53 by HBx has been reported in hepatocytes of HBx transgenic mice (27). The great majority of p53 staining in the livers of hepatocellular carcinoma patients is located in the nuclei of tumor cells (26,28,29). However, in many of these cases, accumulation of nuclear p53 correlates with a mutant p53 genotype, typically a late event in hepatocarcinogenesis (30,31).…”

Section: Resultsmentioning

confidence: 99%

Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis

Elmore

Hancock

Chang

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

300

209

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We have reported previously that the hepatitis B virus oncoprotein, HBx, can bind to the C terminus of p53 and inhibit several critical p53-mediated cellular processes, including DNA sequence-specific binding, transcriptional transactivation, and apoptosis. Recognizing the importance of p53-mediated apoptosis for maintaining homeostasis and preventing neoplastic transformation, here we further examine the physical interaction between HBx and p53 as well as the functional consequences of this association. In vitro binding studies indicate that the ayw and adr viral subtypes of HBx bind similar amounts of glutathione S-transferase-p53 with the distal C terminus of HBx (from residues 111 to 154) being critical for this interaction. Using a microinjection technique, we show that this same C-terminal region of HBx is necessary for sequestering p53 in the cytoplasm and abrogating p53-mediated apoptosis. The transcriptional transactivation domain of HBx also maps to its C terminus; however, a comparison of the ability of full-length and truncated HBx protein to abrogate p53-induced apoptosis versus transactivate simian virus 40-or human nitric oxide synthase-2 promoter-driven reporter constructs indicates that these two functional properties are distinct and thus may contribute to hepatocarcinogenesis differently. Collectively, our data indicate that the distal C-terminal domain of HBx, independent of its transactivation activity, complexes with p53 in the cytoplasm, partially preventing its nuclear entry and ability to induce apoptosis. These pathobiological effects of HBx may contribute to the early stages of hepatocellular carcinogenesis.

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p53 in malignant and benign liver lesions

Cited by 17 publications

References 21 publications

Tissue Microarray Immunohistochemical Profiles of p53 and pRB in Hepatocellular Carcinoma and Hepatoblastoma

Tissue Microarray Immunohistochemical Profiles of p53 and pRB in Hepatocellular Carcinoma and Hepatoblastoma

Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen‐activated protein kinase and JAK/STAT pathways

Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis

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