title: Aspartyl-(asparaginyl) beta-hydroxylase, hypoxia-inducible factor-alpha and Notch cross-talk in regulating neuronal motility.
abstract: Aspartyl-(Asparginyl)-β-Hydroxylase (AAH) promotes cell motility by hydroxylating Notch. Insulin and insulin-like growth factor, type 1 (IGF-I) stimulate AAH through Erk MAPK and phosphoinositol-3-kinase-Akt (PI3K-Akt). However, hypoxia/oxidative stress may also regulate AAH. Hypoxia inducible factor-1 alpha (HIF-1α) regulates cell migration, signals through Notch, and is regulated by hypoxia/oxidative stress, insulin/IGF signaling, and factor inhibiting HIF-1α (FIH) hydroxylation. To examine cross-talk between HIF-1α and AAH, we measured AAH, Notch-1, Jagged-1, FIH, HIF-1α, HIF-1β, and the hairy and enhancer of split 1 (HES-1) transcription factor expression and directional motility in primitive neuroectodermal tumor 2 (PNET2) human neuronal cells that were exposed to H₂O₂, or transfected with short interfering RNA duplexes (siRNA) targeting AAH, Notch-1, or HIF-1α. We found that: 1) AAH, HIF-1α, and neuronal migration were stimulated by H₂O₂; 2) si-HIF-1α reduced AAH expression and cell motility; 3) si-AAH inhibited Notch and cell migration, but not HIF-1α; and 4) si-Notch-1 increased FIH and inhibited HIF-1α. These findings suggest that AAH and HIF-1α cross-talk within a hydroxylation-regulated signaling pathway that may be transiently driven by oxidative stress, and chronically regulated by insulin/IGF signaling.
authors.affiliation: Liver Research Center and Department of Medicine, Rhode Island Hospital, Providence, RI, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: Lawton
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.forename: Fusun
authors.initials: F
authors.lastname: Gundogan
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D012097:Repressor Proteins; D006861:Hydrogen Peroxide; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; C058291:aspartic acid 2-oxoglutarate-dependent dioxygenase