title: Correlation of fragile histidine triad (Fhit) protein structural features with effector interactions and biological functions.
abstract: We have previously shown that Fhit tumor suppressor protein interacts with Hsp60 chaperone machinery and ferredoxin reductase (Fdxr) protein. Fhit-effector interactions are associated with a Fhit-dependent increase in Fdxr stability, followed by generation of reactive oxygen species and apoptosis induction under conditions of oxidative stress. To define Fhit structural features that affect interactions, downstream signaling, and biological outcomes, we used cancer cells expressing Fhit mutants with amino acid substitutions that alter enzymatic activity, enzyme substrate binding, or phosphorylation at tyrosine 114. Gastric cancer cell clones stably expressing mutants that do not bind substrate or cannot be phosphorylated showed decreased binding to Hsp60 and Fdxr and reduced mitochondrial localization. Expression of Fhit or mutants that bind interactor proteins results in oxidative damage and accumulation of cells in G(2)/M or sub-G(1) fractions after peroxide treatment; noninteracting mutants are defective in these biological effects. Gastric cancer clones expressing noncomplexing Fhit mutants show reduction of Fhit tumor suppressor activity, confirming that substrate binding, interaction with heat shock proteins, mitochondrial localization, and interaction with Fdxr are important for Fhit tumor suppressor function.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University and Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okumura
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Preston N
authors.initials: PN
authors.lastname: Garrison
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Sung-Suk
authors.initials: SS
authors.lastname: Suh
authors.forename: Teresa
authors.initials: T
authors.lastname: Druck
authors.forename: Kelly A
authors.initials: KA
authors.lastname: McCorkell
authors.forename: Larry D
authors.initials: LD
authors.lastname: Barnes
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000099170:Bis(5'-adenosyl)triphosphatase