MECHANISMS OF SIGNAL TRANSDUCTION
Identification and Characterization of Presenilin-independent Notch Signaling*

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Presenilin (PS) proteins control the proteolytic cleavage that precedes nuclear access of the Notch intracellular domain. Here we observe that a partial activation of theHES1 promoter can be detected in PS1/PS2 (PS1/2) double null cells using Notch1ΔE constructs or following Delta1 stimulation, despite an apparent abolition of the production and nuclear accumulation of the Notch intracellular domain. PS1/2-independent Notch activation is sensitive to Numblike, a physiological inhibitor of Notch. PS1/2-independent Notch signaling is also inhibited by an active γ-secretase inhibitor in the low micromolar range and is not inhibited by an inactive analogue, similar to PS-dependent Notch signaling. However, experiments using a Notch1-Gal4-VP16 fusion protein indicate that the PS1/2-independent activity does not release Gal4-VP16 and is therefore unlikely to proceed via an intramembranous cleavage. These data reveal that a novel PS1/2-independent mechanism plays a partial role in Notch signal transduction.

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Published, JBC Papers in Press, December 26, 2001, DOI 10.1074/jbc.M108238200

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This work was supported by National Institutes of Health Grants NS35566 (to J. S. N.) and T32GM08061 (to B. E. B.), the Davee Foundation, a Human Frontier Science Program Long Term Fellowship LT-00052/2000-M (to M. K.), and Northwestern University Alzheimer's Disease Center Grant AG13854.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Both authors contributed equally to this work.

**

Present address: Lexicon Genetics, Inc., The Woodlands, TX 77381.