title: Candidate tumor suppressor B-cell translocation gene 3 impedes neoplastic progression by suppression of AKT.
abstract: BTG3 (B-cell translocation gene 3) is a p53 target that also binds and inhibits E2F1. Although it connects two major growth-regulatory pathways functionally and is downregulated in human cancers, whether and how BTG3 acts as a tumor suppressor remain largely uncharacterized. Here we present evidence that BTG3 binds and suppresses AKT, a kinase frequently deregulated in cancers. BTG3 ablation results in increased AKT activity that phosphorylates and inhibits glycogen synthase kinase 3β. Consequently, we also observed elevated β-catenin/T-cell factor activity, upregulation of mesenchymal markers, and enhanced cell migration. Consistent with these findings, BTG3 overexpression suppressed tumor growth in mouse xenografts, and was associated with diminished AKT phosphorylation and reduced β-catenin in tissue specimens. Significantly, a short BTG3-derived peptide was identified, which recapitulates these effects in vitro and in cells. Thus, our study provides mechanistic insights into a previously unreported AKT inhibitory pathway downstream of p53. The identification of an AKT inhibitory peptide also unveils a new avenue for cancer therapeutics development.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: P-H
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: C-S
authors.initials: CS
authors.lastname: Suen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Hwang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, No. 7, Chung Shan S. Road., Taipei 100, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Lin
authors.affiliation: Department of Pathology, National Taiwan University Hospital, No. 7, Chung Shan S. Road., Taipei 100, Taiwan.
authors.forename: P-L
authors.initials: PL
authors.lastname: Lai
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, 128 Section 2, Academia Road, Taipei 115, Taiwan.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Shieh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000201:enzymology; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: C424522:BTG3 protein, human; D018797:Cell Cycle Proteins; D010455:Peptides; D011506:Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3