Direct regulation of intestinal fate by Notch

Stanger, Ben Z.; Datar, Radhika; Murtaugh, L. Charles; Melton, Douglas A.

doi:10.1073/pnas.0505690102

Cited by 264 publications

(225 citation statements)

References 34 publications

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“…Pharmacological inhibition of Notch signaling by nonselective ␥-secretase inhibitors in adult mice has been demonstrated to affect tissue differentiation and cell homeostasis in multiple systems (e.g. gastrointestinal tract, pancreas, skin, and lymphocytes) (11)(12)(13)(14), consistent with predictions from KO mouse models (15)(16)(17)(18)(19)(20)(21)(22). Inhibition of Notch signaling by nonselective ␥-secretase inhibitors is a potentially limiting issue for the clinical development of this class of therapeutics.…”

supporting

confidence: 49%

Identification of γ-Secretase Inhibitor Potency Determinants on Presenilin

Zhao

Neitzel

et al. 2008

Journal of Biological Chemistry

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Production of amyloid ␤ peptides (A␤), followed by their deposition in the brain as amyloid plaques, contributes to the hallmark pathology of Alzheimer disease. The enzymes responsible for production of A␤, BACE1 and ␥-secretase, are therapeutic targets for treatment of Alzheimer disease. Two presenilin (PS) homologues, referred to as PS1 and PS2, comprise the catalytic core of ␥-secretase. In comparing presenilin selectivity of several classes of ␥-secretase inhibitors, we observed that sulfonamides in general tend to be more selective for inhibition of PS1-comprising ␥-secretase, as exemplified by ELN318463 and BMS299897. We employed a combination of chimeric constructs and point mutants to identify structural determinants for PS1-selective inhibition by ELN318463. Our studies identified amino acid residues Leu 172 , Thr 281 , and Leu 282 in PS1 as necessary for PS1-selective inhibition by ELN318463. These residues also contributed in part to the PS1-selective inhibition by BMS299897. Alanine scanning mutagenesis of areas flanking Leu 172 , Thr 281 , and Leu 282 identified additional amino acids that affect inhibitor potency of not only these sulfonamides but also nonsulfonamide inhibitors, without affecting A␤ production and presenilin endoproteolysis. Interestingly, many of these same residues have been identified previously to be important for ␥-secretase function. These findings implicate TM3 and a second region near the carboxyl terminus of PS1 aminoterminal fragment in mediating the activity of ␥-secretase inhibitors. Our observations demonstrate that PS-selective inhibitors of ␥-secretase are feasible, and such inhibitors may allow differential inhibition of A␤ peptide production and Notch signaling.

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supporting

confidence: 49%

Identification of γ-Secretase Inhibitor Potency Determinants on Presenilin

Zhao

Neitzel

et al. 2008

Journal of Biological Chemistry

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“…Our observations provide direct evidence that enteroendocrine cells are specified independently of the Wnt pathway, whereas Paneth cells are not. In contrast to the Wnt, Notch signaling is one pathway that appears to be critical for enteroendocrine lineage specification through its effects on bHLH proteins (6,7). In addition, the ability to activate Wnt target genes via the canonical Wnt pathway may be restricted to immature cells in the intestine and may be lost as cells differentiate.…”

Section: Resultsmentioning

confidence: 99%

Enteroendocrine precursors differentiate independently of Wnt and form serotonin expressing adenomas in response to active β-catenin

Wang

Giel–Moloney

Rindi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The Notch signaling pathway is a key determinant of intestinal epithelial cell self-renewal and allocation of these cells to specific differentiation lineages (Milano et al, 2004;Fre et al, 2005;Stanger et al, 2005;van Es et al, 2005). In mammals, four Notch genes are expressed, each of which encodes a single-pass transmembrane receptor (Notch1-4).…”

Section: Introductionmentioning

confidence: 99%