Targeting promiscuous signaling pathways in cancer: Another Notch in the bedpost

Levi J. Beverly, Anthony J. Capobianco

Research output: Contribution to journalReview article

13 Scopus citations

Abstract

The chromosomal translocation t(7;9)(q34;q34.3) in human T-cell acute lymphoblastic leukemia results in the constitutive activation of Notch (N ic). 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.

Original languageEnglish (US)
Pages (from-to)591-598
Number of pages8
JournalTrends in Molecular Medicine
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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