Modulation of intracellular signal transduction pathways by the hepatitis B virus transactivator pX.
The mechanisms by which pX, the transactivator of the hepatitis B virus (HBV), exerts its effects on transcription of viral and cellular genes and affects cell-growth regulation have not yet been fully defined. Previous reports suggested the possibility of a direct interaction of pX, which lacks intrinsic DNA-binding activity, with components of the cellular transcription machinery. More recent investigations support the hypothesis that pX might activate cellular kinases involved in transcriptional regulation and growth control. We characterized the mechanisms of AP-1 transcription factor activation by pX and, in particular, the role of cellular proteins involved in the intracellular signal transduction of growth-factor receptors. The observation that the overexpression of c-fos and c-jun in the cells results in a clear augmentation of the effects of pX on TRE-directed transcription and the induction of the DNA-binding activity of c-jun/c-fos heterodimers by AP1-depleted nuclear extracts from pX-expressing cells strongly supports the involvement of post-translational modifications. In both HeLa and undifferentiated F9 cells, pX was able to increase the activity of exogenous transfected c-jun but not of c-jun mutants bearing mutations in the serine residues located in the amino-terminal transcriptional activation domain. Moreover, by use of Ha-ras and Raf-1 dominant negative mutants, we show that both Ha-ras and Raf-1 are required for pX-induced activation of c-jun transcriptional activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Natoli
G
G
Istituto di I Clinica Medica, University of Rome, Italy.
Avantaggiati
M L
ML
Chirillo
P
P
De Marzio
E
E
Collepardo
D
D
Falco
M
M
Balsano
C
C
Levrero
M
M
D000818:Animals; D016758:Genes, jun / Q000502:physiology*; D016355:Genes, pX / Q000502:physiology*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D014157:Transcription Factors