Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional γ-Secretase Inhibitor

Searfoss, George H.; Jordan, William H.; Calligaro, David O.; Galbreath, Elizabeth; Schirtzinger, Linda; Berridge, Brian R.; Gao, Hong; Higgins, Marnie A.; May, Patrick C.; Ryan, Timothy P.

doi:10.1074/jbc.m307757200

Cited by 323 publications

(239 citation statements)

References 41 publications

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“…These results are consistent with prior studies using ␥-secretase inhibitors, which nonspecifically block Notch signaling by inhibiting the protease that activates the receptor and cause goblet cell hyperplasia (22)(23)(24). Villus segments exhibiting evidence of prior Cre activity have a relative, rather than absolute, reduction in secretory cells.…”

Section: Labeling Adult Intestinal Progenitor Cells and Misexpressionsupporting

confidence: 81%

Direct regulation of intestinal fate by Notch

Stanger

Datar

Murtaugh

et al. 2005

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

263

209

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The signals that maintain the proper balance between adult intestinal cell types are poorly understood. Loss-of-function studies have implicated the Notch pathway in the regulation of intestinal fate during development. However, it is unknown whether Notch has a role in maintaining the balance of different cell types in the adult intestine and whether it acts reversibly. To determine whether Notch has a direct effect on intestinal development and adult intestinal cell turnover, we have used a gain-of-function approach to activate Notch. Ectopic Notch signaling in adult intestinal progenitor cells leads to a bias against secretory fates, whereas ectopic Notch activation in the embryonic foregut results in reversible defects in villus morphogenesis and loss of the proliferative progenitor compartment. We conclude that Notch regulates adult intestinal development by controlling the balance between secretory and absorptive cell types. In the embryo, Notch activation perturbs morphogenesis, possibly through effects on stem or progenitor cells.differentiation ͉ intestine ͉ lineage ͉ stem cells

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Section: Labeling Adult Intestinal Progenitor Cells and Misexpressionsupporting

confidence: 81%

Direct regulation of intestinal fate by Notch

Stanger

Datar

Murtaugh

et al. 2005

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

263

209

View full text Add to dashboard Cite

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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: 50%

“…Constitutive as well as conditional knock-out mouse studies have demonstrated that mice with selective ablation of different subunits exhibit different severity of Notch-deficient phenotypes, depending upon the age and subunit targeted (10,41,(55)(56)(57)(58)(59)(60)(61)(62). Hence, these studies suggest that isoform-selective inhibitors offer another avenue for circumventing Notch-related toxicity observed with first generation ␥-secretase inhibitors (11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

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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“…Notch blockade via systemic treatment with g-secretase inhibitors such as dibenzazipine (DBZ) causes dose-dependent intestinal metaplasia in animal models (Milano et al 2004). Intestinal crypt stem cells rely on Notch signaling to govern daughter cell fate determination (Searfoss et al 2003), and disruption of Notch in this context leads to overpopulation with mucus-secreting goblet cells, leading to malnutrition and diarrhea.…”

Section: Tips Stalks and Tubesmentioning

confidence: 99%