title: High levels of Notch signaling down-regulate Numb and Numblike.
abstract: Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.
authors.affiliation: Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.forename: Lining
authors.initials: L
authors.lastname: Liu
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
authors.forename: Camilla
authors.initials: C
authors.lastname: Dahlqvist
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D032446:Myoblasts / Q000166:cytology; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch