Direct inhibition of the NOTCH transcription factor complex

Moellering, R.E., et al. Nature. 462, 182-188 (2009)

Speaker: Shi-Yu Chao (趙世宇)                                   Time: 13:00~14:00, Mar. 3, 2010

Commentator: Prof. Woei-Jer Chuang (莊偉哲教授)  Place: Room 601

Abstract

        NOTCH proteins are transmenbrane receptors that regulate cellular differentiation, proliferation and death. When NOTCH is activated upon ligand binding, its intracellular domain (ICN) is released by proteolysis and translocates into the nucleus. The ICN associates with a DNA-bound transcription factor CSL and a co-activator MAML1 to form an ICN-CSL-MAML transcription complex that activates transcription of target genes.^[1] Abnormal NOTCH activation causes many diseases such as T-cell acute lymphoblastic leukaemia (T-ALL).^[2] Small molecules of g-secretase inhibitors (GSIs) can block the proteolysis of NOTCH in T-ALL, however, these molecules are not NOTCH-specific and patients treated with GSIs suffer gastrointestinal toxicity. In this paper, the authors designed a series of stapled alpha-helical peptides derived from MAML1 (SAHMs) and showed that SAHMs acted as NOTCH antagonists. The SAHM1 has stable helical conformation so that it can penetrate from cell membrane into nucleus. The studies showed that SAHM1 can directly bind the NOTCH complex with micromolar affinity by GST pull-down and surface plasmon resonance kinetic assay. When the human T-ALL cell lines were treated with SAHM1, the NOTCH1 transcriptional activity was inhibited and expression of the NOTCH1 target genes was decreased. SAHM1 treatment also inhibited proliferation of T-ALL cells bearing NOTCH mutations for growth. In T-ALL mouse model, mice receiving SAHM1 treatment showed a significant regression of T-ALL as monitored by bioluminescence. Furthermore, expression of the NOTCH1 target genes was decreased in mononuclear cells isolated from SAHM1-treated mice. The data from mouse model demonstrated the inhibition of the NOTCH pathway and anti-leukaemic activity of SAHM1 in vivo. Taken together, SAHM1 inhibits leukaemic progression, triggers global suppression of NOTCH1 signalling and has potential therapeutic value.

References

[1] Bray, S.J. Notch signalling: a simple pathway becomes complex (2006) Nat Rev Mol Cell biol. 7, 678-689.

[2] Onciu, M. Acute lymphoblastic leukemia (2009) Hematol Oncol Clin North Am. 23, 655-674.