|
Anita
Roberts, Ph.D.
Laboratory of Cell Regulation and Carcinogenesis,
National Cancer Inst., Bethesda,
MD
Presented April
5, 2005,
ASBMB Annual Meeting,
San Diego, CA
2005 FASEB Experimental Biology
Symposium
"TGF-beta - journey of discovery and
promise"
(Click above for a 14 Meg Video Stream
of entire lecture)
In the nearly 20 years since the discovery and
initial characterization of TGF-b, it has emerged as the
paradigmatic growth factor, defining the cell- and context-specific actions now
attributed to many growth factors. TGF-b1, initially
characterized in 1983, was the first of what is now known to be a large family
of over 40 structurally related growth factors including the
activins and bone morphogenetic proteins. All of the members of the TGF-b superfamily signal through pairs of type
I and II transmembrane receptor serine-threonine
kinases
and share downstream signaling mediators called Smad
proteins. Important roles for TGF-b
have been defined in wound healing and in the pathogenesis of diseases ranging
from autoimmune disease, to fibrosis, to cancer.
Contributing to these activities are a range of molecular mechanisms
including the inhibition of growth of cells of epithelial and lymphoid origin,
stimulation of production of extracellular matrix by
mesenchymal
cells, induction of chemotaxis, regulation of
apoptosis, and the initiation of epithelial-to-mesenchymal
transition.
The context-specific actions of TGF-b
are particularly evident in carcinogenesis where the protein plays both a tumor
suppressor role in the early stages of disease and a pro-metastatic
role in later stages. New insights into the role of this protein in disease
processes are now leading to development of novel therapeutic strategies based
on interference with the ligand, the receptor, or the
downstream Smad signaling pathway. These strategies are providing great
promise for new clinical approaches to the treatment of a range of disorders in
which TGF-b
plays a prominent role.
|
