Targeting promiscuous signaling pathways in cancer: another Notch in the bedpost.
The chromosomal translocation t(7;9)(q34;q34.3) in human T-cell acute lymphoblastic leukemia results in the constitutive activation of Notch (Nic). Reported mutations in Ikaros cause the loss of DNA-binding, which in turn leads to a loss of repressive activity. Recently, these two mutations have been shown to cooperate in leukemogenesis. The current model proposes that the combination of the loss of Ikaros activity and the gain of constitutive Notch activity disrupts the normal balance between repression and activation at common regulatory elements. Furthermore, the model is extended to suggest that multiple transcription factors coordinate transcriptional repression and activation through these common regulatory elements. In leukemogenesis, the breakdown of this coordinate regulation underlies one of the pathophysiological mechanisms. Finally, using Notch as a template, potential points of interdiction by designer therapeutics are discussed.
Beverly
Levi J
LJ
The Wistar Institute, Molecular and Cellular Oncogenesis Program, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Capobianco
Anthony J
AJ
D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051740:Ikaros Transcription Factor; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; D051740:Ikaros Transcription Factor