INVESTIGADORES
SREBROW Anabella
artículos
Título:
Mammary epithelial-mesenchymal interaction regulates fibronectin alternative splicing via phosphatidylinositol 3-kinase
Autor/es:
BLAUSTEIN MATIAS; PELISCH FEDERICO; COSO OMAR; BISSELL MINA J; KORNBLIHTT ALBERTO R; SREBROW ANABELLA
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
The American Society of Biochemistry and Molecular biology
Referencias:
Año: 2004 vol. 279 p. 21029 - 21037
ISSN:
0021-9258
Resumen:
The way alternative splicing is regulated within tissues
is not understood. A relevant model of this process
is provided by fibronectin, an important extracellular
matrix protein that plays a key role in cell adhesion and
migration and contains three alternatively spliced regions
known as EDI, EDII, and IIICS. We used a cell
culture system to simulate mammary epithelial-stromal
communication, a process that is crucial for patterning
and function of the mammary gland, and studied the
effects of extracellular signals on the regulation of fibronectin
pre-mRNA alternative splicing. We found that
soluble factors from a mammary mesenchymal cell-conditioned
medium, as well as the growth factors HGF/SF
(hepatocyte growth factor/scatter factor), KGF (keratinocyte
growth factor), and aFGF (acidic fibroblast
growth factor), stimulate EDI and IIICS but not EDII
inclusion into fibronectin mRNA in the mammary epithelial
cell line SCp2, favoring fibronectin isoforms associated
with proliferation, migration, and tissue remodeling.
We explored the signaling pathways involved
in this regulation and found that the mammary mesenchymal
cell-conditioned medium and HGF/SF act
through a phosphatidylinositol 3-kinase-dependent cascade
to alter fibronectin alternative splicing. This splicing
regulation is independent from promoter structure
and de novo protein synthesis but does require two exonic
elements within EDI. These results shed light on
how extracellular stimuli are converted into changes in
splicing patterns.