Volume 270,
Number 17,
Issue of April 28, pp. 10204-10211, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
The
c- jun Proto-oncogene Down-regulates the Rat
-Fetoprotein
Promoter in HepG2 Hepatoma Cells without Binding to DNA
Brigitte
Bois-Joyeux
,
Mikhail
Denissenko
,
Hélène
Thomassin
,
Sophie
Guesdon
,
Raina
Ikonomova
,
Dominique
Bernuau
,
Gérard
Feldmann
,
Jean-Louis
Danan
The effects of a phorbol ester (TPA) and of members of the Jun
and Fos oncoprotein family on the activity of the rat
-fetoprotein
(AFP) promoter were checked by using transient expression experiments
in HepG2 hepatoma cells. TPA blocked the activity of the rat AFP
promoter in a dose-dependent manner. Overexpression of c-Jun
specifically repressed the rat AFP promoter but not the albumin
promoter. JunB and JunD were poorer inhibitors. c-Fos expression did
not potentiate the negative effect of Jun. The Jun-induced repression
does not require binding of c-Jun to the AFP promoter. DNase 1
footprinting experiments did not display any high affinity binding site
for Jun on the AFP promoter. Integrity of the c-Jun DNA binding domain
is not required for the c-Jun protein to block the AFP promoter. The
N-terminal part of Jun, which contains the activating domain, is
responsible for the repression as shown by using Jun-Gal4 chimera. Jun
likely exerts its negative control on the AFP promoter via
protein-protein interactions with a not yet identified
trans-activating factor within the -134 to +6
region or with a component of the general machinery of transcription.
Jun proteins can thus be key intermediates in regulatory cascades which
result in the differential modulation of the AFP and albumin gene
expression in the course of liver development and carcinogenesis.