Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis.
TGF-beta 1 has been implicated in the pathogenesis of liver disease. The high frequency of detection of the hepatitis B virus X (HBx) antigen in liver cells from patients with chronic hepatitis, cirrhosis, and liver cancer suggested that expression of HBx and TGF-beta 1 may be associated. To test this possibility, we examined the expression of TGF-beta 1 in the liver of transgenic mice expressing the HBx gene. We show that the patterns of expression of TGF-beta 1 and Hbx protein are similar in these mice and that HBx activates transcription of the TGF-beta 1 gene in transfected hepatoma cells. The cis-acting element within the TGF-beta 1 gene that is responsive to regulation by Hbx is the binding site for the Egr family of transcription factors. We further show that the Egr-1 protein associates with the HBx protein, allowing HBx to participate in the transcriptional regulation of immediate-early genes. Our results suggest that expression of Hbx might induce expression of TGF-beta 1 in the early stages of infection and raise the possibility that TGF-beta 1 may play a role in hepatitis B virus pathogenesis.
Yoo
Y D
YD
Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892, USA.
Ueda
H
H
Park
K
K
Flanders
K C
KC
Lee
Y I
YI
Jay
G
G
Kim
S J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D015967:Gene Expression Regulation, Viral; D006511:Hepatitis B Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000472:pathogenicity*; D017874:Immediate-Early Proteins; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006511:Hepatitis B Antigens; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein