INVESTIGADORES
GUBERMAN Alejandra Sonia
artículos
Título:
Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways.
Autor/es:
GUBERMAN AS, SCASSA ME, CANEPA ET.
Revista:
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Referencias:
Año: 2005 vol. 436 p. 285 - 296
ISSN:
0003-9861
Resumen:
The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA)
induces activator protein-1 (AP-1) transcription factors, early
response genes involved in a diverse set of transcriptional regulatory
processes, and protein kinase C (PKC) activity. This work was designed
to explore the signal transduction pathways involved in TPA regulation
of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial
matrix enzyme that catalyzes the first and rate-limiting step of heme
biosynthesis. We have previously reported that TPA causes repression of
ALAS gene, but the signaling pathways mediating this effect remain
elusive. The present study investigates the role of different cascades
often implicated in the propagation of phorbol ester signaling. To
explore this, we combined the transient overexpression of regulatory
proteins involved in these pathways and the use of small cell permeant
inhibitors in human hepatoma HepG2 cells. In these experimental
conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as
well as the promoter activity of a fusion reporter construct, harboring
the TPA-responsive region of ALAS gene driving chloramphenicol acetyl
transferase gene expression. We demonstrated that the participation of
alpha isoform of PKC, phosphatidylinositol 3-kinase (PI3K),
extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal
kinase (JNK) is crucial for the end point response. Remarkably, in this
case, ERK activation is achieved in a Ras/Raf/MEK-independent manner.
We also propose that p90RSK would be a convergent point between PI3K
and ERK pathways. Furthermore, we elucidated the crosstalk among the
components of the cascades taking part in TPA-mediated ALAS repression.
Finally, by overexpression of a constitutively active p90RSK and the
coactivator, cAMP-response element protein (CREB)-binding protein
(CBP), we reinforced our previous model, that implies competition
between AP-1 and CREB for CBP.