title: TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death.
abstract: Self-aggregation of transforming growth factor β (TGF-β)1-induced antiapoptotic factor (TIAF1) is known in the nondemented human hippocampus, and the aggregating process may lead to generation of amyloid β (Aβ) for causing neurodegeneration. Here, we determined that overexpressed TIAF1 exhibits as aggregates together with Smad4 and Aβ in the cancer stroma and peritumor capsules of solid tumors. Also, TIAF1/Aβ aggregates are shown on the interface between brain neural cells and the metastatic cancer cell mass. TIAF1 is upregulated in developing tumors, but may disappear in established metastatic cancer cells. Growing neuroblastoma cells on the extracellular matrices from other cancer cell types induced production of aggregated TIAF1 and Aβ. In vitro induction of TIAF1 self-association upregulated the expression of tumor suppressors Smad4 and WW domain-containing oxidoreductase (WOX1 or WWOX), and WOX1 in turn increased the TIAF1 expression. TIAF1/Smad4 interaction further enhanced Aβ formation. TIAF1 is known to suppress SMAD-regulated promoter activation. Intriguingly, without p53, self-aggregating TIAF1 spontaneously activated the SMAD-regulated promoter. TIAF1 was essential for p53-, WOX1- and dominant-negative JNK1-induced cell death. TIAF1, p53 and WOX1 acted synergistically in suppressing anchorage-independent growth, blocking cell migration and causing apoptosis. Together, TIAF1 shows an aggregation-dependent control of tumor progression and metastasis, and regulation of cell death.
authors.affiliation: Institute of Molecular Medicine, National Cheng Kung University College of Medicine, Tainan, Taiwan, ROC.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Chang
authors.forename: M-F
authors.initials: MF
authors.lastname: Chiang
authors.forename: S-R
authors.initials: SR
authors.lastname: Lin
authors.forename: M-H
authors.initials: MH
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: He
authors.forename: P-Y
authors.initials: PY
authors.lastname: Chou
authors.forename: S-J
authors.initials: SJ
authors.lastname: Chen
authors.forename: Y-A
authors.initials: YA
authors.lastname: Chen
authors.forename: L-Y
authors.initials: LY
authors.lastname: Yang
authors.forename: F-J
authors.initials: FJ
authors.lastname: Lai
authors.forename: C-C
authors.initials: CC
authors.lastname: Hsieh
authors.forename: T-H
authors.initials: TH
authors.lastname: Hsieh
authors.forename: H-M
authors.initials: HM
authors.lastname: Sheu
authors.forename: C-I
authors.initials: CI
authors.lastname: Sze
authors.forename: N-S
authors.initials: NS
authors.lastname: Chang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002465:Cell Movement; D002522:Chlorocebus aethiops; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase; D009218:Myosins
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D048055:Mitogen-Activated Protein Kinase 8; D009687:Nuclear Proteins; D010088:Oxidoreductases; D051901:Smad4 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; C407152:MYO18A protein, human; D009218:Myosins; C486071:WWOX protein, human