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Vol. 14, No. 20, pp. 2610-2622, October 15, 2000
production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells
1 Signal Transduction and 2 Developmental
Signaling Laboratories, Imperial Cancer Research Fund, London WC2A 3PX,
UK; 3 Institute of Molecular Pathology, A-1030 Vienna,
Austria; 4 Cancer Research Institute, UCSF/Mt. Zion Cancer
Center, San Francisco, California 94115-0128, USA
c-Raf-1 is a major effector of Ras proteins, responsible for
activation of the ERK MAP kinase pathway and a critical regulator of
both normal growth and oncogenic transformation. Using an inducible form of Raf in MDCK cells, we have shown that sustained activation of
Raf alone is able to induce the transition from an epithelial to a
mesenchymal phenotype. Raf promoted invasive growth in collagen gels, a
characteristic of malignant cells; this was dependent on the operation
of an autocrine loop involving TGF
, whose secretion was induced by
Raf. TGF induced growth inhibition and apoptosis in normal MDCK
cells: Activation of Raf led to inhibition of the ability of TGF
to induce apoptosis but not growth retardation. ERK has been reported
previously to inhibit TGF signaling via phosphorylation of the
linker region of Smads, which prevents their translocation to the
nucleus. However, we found no evidence in this system that ERK can
significantly influence the function of Smad2, Smad3, and Smad4 at the
level of nuclear translocation, DNA binding, or transcriptional
activation. Instead, strong activation of Raf caused a broad protection
of these cells from various apoptotic stimuli, allowing them to respond
to TGF with increased invasiveness while avoiding cell death. The
Raf-MAP kinase pathway thus synergizes with TGF in promoting
malignancy but does not directly impair TGF-induced Smad signaling.
[Key Words:
Ras; Raf; TGF; SMAD; apoptosis]
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