INVESTIGADORES
COSTAS Monica Alejandra
artículos
Título:
The steroid receptor co-activator-1 (SRC-1) potentiates TGF-?/Smad signaling: Role of p300/CBP
Autor/es:
DENNLER S; PENDARIES V; TACHEAU C; MONICA ALEJANDRA COSTAS; MAUVIEL A; VERRECCHIA F
Revista:
Oncogene
Referencias:
Año: 2004 vol. 24 p. 1936 - 1945
ISSN:
0950-9232
Resumen:
The three related 160-kDa proteins, SRC-1, TIF-2 and
RAC-3, were initially identied as factors interacting with
nuclear receptors. They have also been reported to
potentiate the activity of other transcription factors such
as AP-1 or NF-jB. The aimof this work was to identify
whether SRC-1 interferes with the TGF-b/Smad signaling
pathway, and if so, to identify its underlying mechanisms
of action. Using transient cell transfection experiments
performed in human dermal broblasts with the Smad3/4-
specic (SBE)4-lux reporter construct, as well as the
human PAI-1 promoter, we determined that SRC-1
enhances TGF-b-induced, Smad-mediated, transcription.
Likewise, SRC-1 overexpression potentiated TGF-binduced
upregulation of PAI-1 steady-state mRNA levels.
Using a mammalian two-hybrid system, we demonstrated
that SRC-1 interacts with the transcriptional co-activators
p300/CBP, but not with Smad3. Overexpression of
the adenovirus E1A oncoprotein, an inhibitor of CBP/
p300 activity, prevented the enhancing effect of SRC-1 on
Smad3/4-mediated transcription, indicating that p300/
CBP may be required for SRC-1 effect. Such hypothesis
was validated, as expression of a mutant form of SRC-1
lacking the CBP/p300-binding site failed to upregulate
Smad3/4-dependent transcription, while full-length SRC-
1 potentiated p300 . Smad3 interactions. These results
identify SRC-1 as a novel Smad3/4 transcriptional
partner, facilitating the functional link between Smad3
and p300/CBP.