title: Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells.
abstract: Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells. In this study, we report the discovery of a ubiquitin-like (UBX)-domain-containing protein, UBXN2A, which binds to mot-2 and consequently inhibits the binding between mot-2 and p53. Genetic analysis showed that UBXN2A binds to mot-2's substrate binding domain, and it partly overlaps p53's binding site indicating UBXN2A and p53 likely bind to mot-2 competitively. By binding to mot-2, UBXN2A releases p53 from cytosolic sequestration, rescuing the tumor suppressor functions of p53. Biochemical analysis and functional assays showed that the overexpression of UBXN2A and the functional consequences of unsequestered p53 trigger p53-dependent apoptosis. Cells expressing shRNA against UBXN2A showed the opposite effect of that seen with UBXN2A overexpression. The expression of UBXN2A and its apoptotic effects were not observed in normal colonic epithelial cells and p53-/- colon cancer cells. Finally, significant reduction in tumor volume in a xenograft mouse model in response to UBXN2A expression was verified in vivo. Our results introduce UBXN2A as a home defense response protein, which can reconstitute inactive p53-dependent apoptotic pathways. Inhibition of mot-2-p53 interaction by UBXN2A is an attractive therapeutic strategy in mot-2-elevated tumors.
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sane
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Abdullah
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Boudreau
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Autenried
authors.affiliation: Department of Pharmaceutical Sciences, Cancer Research Center, University of Tennessee Health Science Center, 19S Manassas Avenue, Memphis, TN, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Gupta
authors.affiliation: Departments of Physiology & Biophysics, University of California, Irvine, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: E H
authors.initials: EH
authors.lastname: Schlenker
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Telleria
authors.affiliation: Departments of Physiology & Biophysics, University of California, Irvine, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutical Sciences, Cancer Research Center, University of Tennessee Health Science Center, 19S Manassas Avenue, Memphis, TN, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chauhan
authors.affiliation: Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Rezvani
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D001667:Binding, Competitive; D053148:Caspase 3 / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D045325:HCT116 Cells; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C000609706:UBXN2A protein, human; C515819:UBXN4 protein, human; D014452:Ubiquitins; C505407:CASP3 protein, human; D053148:Caspase 3