Chemotherapeutic drug, adriamycin, restores the function of p53 protein in hepatitis B virus X (HBx) protein-expressing liver cells.
Hepatitis B virus X (HBx) protein implicated in the development of liver cancer may inhibit the function of p53 tumor suppressor protein through cytoplasmic retention of p53 protein. Here, we attempt to investigate whether the functional inhibition of p53 protein by HBx protein is reversible. First, we provide the evidence for the association of endogenous p53 protein with HBx by co-immunoprecipitation in stable Chang cells that express HBx protein in an inducible manner (ChangX-34). By immunofluorescence microscopy, the major location of p53 protein of ChangX-34 cells was confirmed at the nuclear periphery as well as in the cytoplasm where HBx protein is mainly expressed. Surprisingly, anticancer drug, adriamycin induces the nuclear translocation of p53 protein sequestered in the cytoplasm. This change is accompanied by the restoration of p53 activity, which results in increased transcriptional activity at the p53-responsive DNA elements as well as increase of p21WAF1 mRNA expression. Further, we observed the induction of cell death and G1 arrest in these cells upon adriamycin treatment regardless of HBx expression. Together, we demonstrate that functional inhibition of p53 protein through its cytoplasmic retention by HBx protein is reversible. These results may be extended into other tumors of which p53 activity is modulated by viral oncoproteins.
Yun
C
C
Department of Biochemistry, Ajou University School of Medicine, Wonchon-dong 5, Paldal-ku, Suwon 442-749, Korea.
Lee
J H
JH
Park
H
H
Jin
Y M
YM
Park
S
S
Park
K
K
Cho
H
H
D000970:Antineoplastic Agents / Q000494:pharmacology; D002451:Cell Compartmentation; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D006511:Hepatitis B Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
D000970:Antineoplastic Agents; D006511:Hepatitis B Antigens; D011994:Recombinant Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004317:Doxorubicin