Activation of fibronectin gene expression by hepatitis B virus x antigen.
The development of fibrosis and cirrhosis during chronic hepatitis B virus (HBV) infection correlates with the persistent expression of HBV x antigen (HBxAg), which acts in part, by stimulating selected signal transduction pathways, including nuclear factor kappa B (NF-kappa B). To identify NF-kappa B responsive genes that are differentially expressed in HBxAg-positive cells, HepG2 cells were stably transfected with HBxAg, and then with pZeoSV2 or pZeoSV2-I kappa B alpha. When RNAs from each culture were compared by PCR-select cDNA subtraction, fibronectin (FN) mRNA was shown to be strongly down-regulated by I kappa B alpha. Up-regulated expression of FN and co-expression between FN and HBxAg were observed in liver sections from HBV carriers that were stained for HBxAg and analysed for FN mRNA by in situ hybridization (ISH). In liver cell cultures, HBxAg increased the levels of FN mRNA and protein. This was because of the HBxAg-mediated trans-activation of the FN promoter, which was NF-kappa B-dependent. HBxAg also antagonized the repression of the FN promoter by the tumour suppressor, p53. Hence, the FN gene may be a natural target for HBxAg trans-activation, perhaps through activation of NF-kappa B and inactivation of p53, thereby contributing to the accumulation of FN in the liver over the course of chronic HBV infection.
Norton
P A
PA
Department of Biochemistry and Molecular Pharmacology, Jefferson Center for Biomedical Research, Thomas Jefferson University, Philadelphia, PA 18901, USA. pamela.norton@jefferson.edu
Reis
H M G P V
HM
Prince
S
S
Larkin
J
J
Pan
J
J
Liu
J
J
Gong
Q
Q
Zhu
M
M
Feitelson
M A
MA
D002460:Cell Line; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D006515:Hepatitis B virus / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000503:physiopathology* / Q000821:virology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008099:Liver / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000302:isolation & purification; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors; D054334:Viral Regulatory and Accessory Proteins
D005353:Fibronectins; D016328:NF-kappa B; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein