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Vol. 12, Issue 4, 863-879, April 2001
Rochelle Belfer Chemotherapy Foundation Laboratory, Division of
Medical Oncology, Department of Medicine, Mount Sinai School of
Medicine, New York, New York 10029
We discovered that a shift between the state of
tumorigenicity and dormancy in human carcinoma (HEp3) is attained
through regulation of the balance between two classical
mitogen-activated protein kinase (MAPK)-signaling pathways, the
mitogenic extracellular regulated kinase (ERK) and the apoptotic/growth
suppressive stress-activated protein kinase 2 (p38MAPK), and that urokinase plasminogen activator
receptor (uPAR) is an important regulator of these events. This is a
novel function for uPAR whereby, when expressed at high level, it
enters into frequent, activating interactions with the
5
1-integrin, which facilitates the formation of insoluble
fibronectin (FN) fibrils. Activation of 51-integrin by
uPAR generates persistently high level of active ERK necessary for
tumor growth in vivo. Our results show that ERK
activation is generated through a convergence of two pathways: a
positive signal through uPAR-activated 51, which activates ERK,
and a signal generated by the presence of FN fibrils that suppresses
p38 activity. When fibrils are removed or their assembly is blocked,
p38 activity increases. Low uPAR derivatives of HEp3 cells, which are
growth arrested (dormant) in vivo, have a high p38/ERK activity ratio,
but in spite of a similar level of 51-integrin, they do
not assemble FN fibrils. However, when p38 activity is inhibited by
pharmacological (SB203580) or genetic (dominant negative-p38)
approaches, their ERK becomes activated, uPAR is overexpressed,
51-integrins are activated, and dormancy is interrupted.
Restoration of these properties in dormant cells can be mimicked by a
direct re-expression of uPAR through transfection with a uPAR-coding
plasmid. We conclude that overexpression of uPAR and its interaction
with the integrin are responsible for generating two feedback
loops; one increases the ERK activity that feeds back by increasing the
expression of uPAR. The second loop, through the presence of FN
fibrils, suppresses p38 activity, further increasing ERK activity.
Together these results indicate that uPAR and its interaction with the
integrin should be considered important targets for induction
of tumor dormancy.
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