The intracellular form of notch blocks transforming growth factor beta-mediated growth arrest in Mv1Lu epithelial cells.
Notch signaling influences a variety of cell fate decisions during development, and constitutive activation of the pathway can provoke unbridled cell growth and cancer. The mechanisms by which Notch affects cell growth are not well established. We describe here a novel link between Notch and cell cycle control. We found that Mv1Lu epithelial cells harboring an oncogenic form of Notch (NICD) are resistant to the cell cycle-inhibitory effects of transforming growth factor beta (TGF-beta). NICD did not affect TGF-beta signaling per se but blocked induction of the Cdk inhibitor p15(INK4B). c-Myc, whose down-regulation by TGF-beta is required for p15(INK4B) induction, remained elevated in the NICD-expressing cells. c-Myc expression was also maintained in low serum, indicating that Notch's effects on c-Myc are not specific to TGF-beta. Our results are consistent with a model in which a strong Notch signal indirectly deregulates c-Myc expression and thereby renders Mv1Lu epithelial cells resistant to growth-inhibitory signals.
Rao
Prakash
P
Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
Kadesch
Tom
T
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D016259:Genes, myc; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch; D015398:Signal Transduction; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008565:Membrane Proteins; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins