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Comment
. 2009 Jan;15(1):20-1.
doi: 10.1038/nm0109-20.

Gamma-secretase inhibitors: Notch so bad

Gerard C Grosveld
Comment

Gamma-secretase inhibitors: Notch so bad

Gerard C Grosveld. Nat Med. 2009 Jan.
No abstract available

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Figures

Figure 1
Figure 1. Combined treatment of NOTCH-positive T-ALL with a γ-secretase inhibitor and dexamethasone
In untreated T-cells with mutant NOTCH (yellow dot), ICN1 released by γ-secretase associates with the transcription factor CSL and upregulates expression of the NOTCH target HES1. HES1 binding to the promoter of the NC3C1 gene inhibits its expression and results in insufficient production of the encoded glucocorticoid receptor- rendering these cells resistant to treatment with dexamethasone. Treatment with γ-secretase inhibitor and deamethasone prevents the release of ICN and CSL remains associated with a repressor complex, inhibiting HES1 expression. The inhibitor thereby restores autoinduction of the glucocorticoid receptor in the presence of dexamethasone and activates expression of its target genes, including BCL2L11. Increased amount of the proapoptotic BIM protein induces apoptosis, which eliminates the NOTCH-activated T-cells.
See this image and copyright information in PMC

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