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Review
. 2011 Nov 30:11:502.
doi: 10.1186/1471-2407-11-502.

Current views on the role of Notch signaling and the pathogenesis of human leukemia

Joanna Pancewicz  1 , Christophe Nicot
Affiliations
Review

Current views on the role of Notch signaling and the pathogenesis of human leukemia

Joanna Pancewicz et al. BMC Cancer. .

Abstract

The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.

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Figures

Figure 1
Figure 1
Structure of the four human Notch receptors. NEC: extracellular subunit; NTM: transmembrane subunit; EGF: epidermal growth factor; HD: heterodimerization domain; ICN: intracellular domain; LNR: cysteine-rich LNR repeats; TM: transmembrane domain; RAM: RAM domain; NLS: nuclear localizing signals; ANK: ankyrin repeat domain; NCR: cysteine response region; TAD: transactivation domain; PEST: region rich in proline (P), glutamine (E), serine (S) and threonine (T) residues.
Figure 2
Figure 2
The Notch signaling pathway. The initiation of the Notch signaling pathway begins when the Notch ligand binds to the Notch receptor. This action triggers two proteolytic cleavages by ADAM-type protease (S2) and γ-secretase (S3), respectively. Following cleavages, the activated form of Notch is released (NICD) and is translocated to the nucleus, where NICD forms complexes with specific DNA-binding proteins (CBF1/Suppressor of Hairless/LAG-1 and Mastermind/SEL-8). Afterward the transcriptional process of target genes is initiated. MAML1: Mastermind-like 1 protein; CBF1: DNA-binding transcription factor.
Figure 3
Figure 3
Noncanonical Notch signaling pathway. (A) NICD-dependent, CBF1-independent transcriptional activation by NICD, coactivators and other undefined factors (B) Interaction of NICD with components of other signaling pathways to activate Notch targets or tissue-specific factors.
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