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J. Biol. Chem., Vol. 278, Issue 18, 16405-16413, May 2, 2003
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From the Center for Molecular Medicine, Maine Medical Center
Research Institute, Scarborough, Maine 04074
Aberrant activations of the Notch and fibroblast
growth factor receptor (FGFR) signaling pathways have been correlated
with neoplastic growth in humans and other mammals. Here we report that
the suppression of Notch signaling in NIH 3T3 cells by the expression
of either the extracellular domain of the Notch ligand Jagged1 or
dominant-negative forms of Notch1 and Notch2 results in the
appearance of an exaggerated fibroblast growth factor
(FGF)-dependent transformed phenotype characterized by
anchorage-independent growth in soft agar. Anchorage-independent growth
exhibited by Notch-repressed NIH 3T3 cells may result from prolonged
FGFR stimulation caused by both an increase in the expression of
prototypic and oncogenic FGF gene family members and the nonclassical
export of FGF1 into the extracellular compartment. Interestingly, FGF
exerts a negative effect on Notch by suppressing CSL
(CBF-1/RBP-Jk/KBF2 in mammals, Su(H) in
Drosophila and Xenopus, and Lag-2
in Caenorhabditis elegans)-dependent transcription, and the ectopic expression of constitutively active forms of Notch1 or Notch2 abrogates FGF1 release and the phenotypic effects of FGFR stimulation. These data suggest that
communication between the Notch and FGFR pathways may represent an
important reciprocal autoregulatory mechanism for the regulation of
normal cell growth.
Notch Activation Suppresses Fibroblast Growth
Factor-dependent Cellular Transformation*
§,,
*
This work was supported in part by National Institutes of
Health Grants CA92255 (to D. S.), HL32348 and HL35627 (to T. M.), and
RR15555 (to T. M. and L. L.) and by American Cancer Society Grant
RPG97-093-03 (to L. L.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Both authors contributed equally to this work.
§
Present address: Dept. of Animal, Nutritional and Medical
Laboratory Sciences, College of Life Sciences and Agriculture,
University of New Hampshire, Durham, NH 03824.
¶
To whom correspondence should be addressed: Center for
Molecular Medicine, Maine Medical Center Research Institute, 81 Research Dr., Scarborough, ME 04074. Tel.: 207-885-8200; Fax:
207-885-8179; E-mail: maciat@mmc.org.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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