Notch activation suppresses fibroblast growth factor-dependent cellular transformation.
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.
Small
Deena
D
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
Kovalenko
Dmitry
D
Soldi
Raffaella
R
Mandinova
Anna
A
Kolev
Vihren
V
Trifonova
Radiana
R
Bagala
Cinzia
C
Kacer
Doreen
D
Battelli
Chiara
C
Liaw
Lucy
L
Prudovsky
Igor
I
Maciag
Thomas
T
D016475:3T3 Cells; D000818:Animals; D002135:Calcium-Binding Proteins; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D029721:Drosophila Proteins; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008562:Membrane Glycoproteins / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D014176:Protein Biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D029867:Xenopus Proteins
C423451:CSL receptor, human; D002135:Calcium-Binding Proteins; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D051880:Receptors, Notch; C000606278:Ser protein, Drosophila; D000072099:Serrate-Jagged Proteins; D029867:Xenopus Proteins; C000606280:jag1 protein, Xenopus; D016220:Fibroblast Growth Factor 1