title: A nanotechnological, molecular-modeling, and immunological approach to study the interaction of the anti-tumorigenic peptide p28 with the p53 family of proteins.
abstract: p28 is an anionic, amphipathic, cell-penetrating peptide derived from the cupredoxin azurin that binds to the DNA-binding domain (DBD) of the tumor suppressor protein, p53, and induces a post-translational increase in the level of wild type and mutated p53 in a wide variety of human cancer cells. As p63 and p73, additional members of the p53 superfamily of proteins, also appear to be involved in the cellular response to cancer therapy and are reportedly required for p53-induced apoptosis, we asked whether p28 also binds to p63 and p73. Atomic force spectroscopy demonstrates that p28 forms a stable, high-affinity complex with full-length p63, the DBD of p63, and full-length p73. Exposure to p28 decreased the level of TAp63α and ΔNp63α, the truncated form of p63, in p53 wild type and mutated human breast cancer cells, respectively. p28 increased the level of TAp73α, but not ΔNp73α, in the same breast cancer cell lines. In contrast, p28 increased the level of the TA and ΔN isoforms of p63 in p53 wild type, but not in p53 mutated melanoma cells, while decreasing TA p73α in p53 wild type and mutated human melanoma cells. All changes were mirrored by an associated change in the expression of the HECT E3 ligases Itch/AIP4, AIP5, and the RING E3 ligase Pirh2, but not in the receptor for activated C kinase or the RING E3 ligases Mdm2 and Cop1. Collectively, the data suggest that molecules such as p28 bind with high affinity to the DBD of p63 and p73 and alter their expression independent of the Mdm2 and Cop1 pathways.
authors.affiliation: Biophysics and Nanoscience Centre, CNISM-DEB, Università della Tuscia, Viterbo, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Coppari
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Biophysics and Nanoscience Centre, CNISM-DEB, Università della Tuscia, Viterbo, Italy.
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bizzarri
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of Illinois College of Medicine, Chicago, IL, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Beattie
authors.affiliation: Biophysics and Nanoscience Centre, CNISM-DEB, Università della Tuscia, Viterbo, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cannistraro
mesh_terms: D000970:Antineoplastic Agents / Q000276:immunology; D001400:Azurin / Q000737:chemistry* / Q000276:immunology* / Q000648:ultrastructure; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D018448:Models, Immunological; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology* / Q000648:ultrastructure; D011485:Protein Binding; D025941:Protein Interaction Mapping; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D001400:Azurin; C561466:azurin (50-77)
keywords: anticancer peptide; molecular interaction; p53 superfamily of proteins
references.citation: J Biol Chem. 2011 Apr 8;286(14):12033-41
references.pmid: 21317427
references.citation: Cell Cycle. 2010 Nov 15;9(22):4584-91
references.pmid: 21088494
references.citation: J Mol Recognit. 2008 Jan-Feb;21(1):63-70
references.pmid: 18247358
references.citation: J Biol Chem. 2005 Aug 5;280(31):28203-14
references.pmid: 15919663
references.citation: Mol Cell Biol. 1992 Dec;12(12):5581-92
references.pmid: 1448088
references.citation: Proteins. 2010 Nov 15;78(15):3124-30
references.pmid: 20818657
references.citation: FEBS Lett. 2012 May 21;586(10):1397-402
references.pmid: 22673504
references.citation: J Cell Sci. 2000 May;113 ( Pt 10):1661-70
references.pmid: 10769197
references.citation: Cell Mol Life Sci. 2012 May;69(9):1425-34
references.pmid: 22051607
references.citation: Carcinogenesis. 2004 Jun;25(6):857-64
references.pmid: 15033906
references.citation: Colloids Surf B Biointerfaces. 2006 Dec 1;53(2):149-56
references.pmid: 17023148
references.citation: Cell Death Differ. 2006 Jun;13(6):890-7
references.pmid: 16543939
references.citation: Cancer Res. 2009 Jan 15;69(2):537-46
references.pmid: 19147567
references.citation: Chem Soc Rev. 2010 Feb;39(2):734-49
references.pmid: 20111790
references.citation: Mol Cancer Res. 2011 Dec;9(12):1780-90
references.pmid: 21994467
references.citation: Cell Cycle. 2006 Aug;5(16):1735-9
references.pmid: 16931910
references.citation: Cell Cycle. 2004 Oct;3(10):1285-95
references.pmid: 15467455
references.citation: Cell Death Differ. 2011 Sep;18(9):1487-99
references.pmid: 21760596
references.citation: J Invest Dermatol. 2013 May;133(5):1178-87
references.pmid: 23235527
references.citation: J Mol Recognit. 2009 Nov-Dec;22(6):506-15
references.pmid: 19642109
references.citation: Nature. 2000 Oct 5;407(6804):642-5
references.pmid: 11034214
references.citation: Drug Resist Updat. 2008 Aug-Oct;11(4-5):152-63
references.pmid: 18801697
references.citation: Mol Pharm. 2013 Sep 3;10(9):3375-83
references.pmid: 23952735
references.citation: Nature. 1999 Apr 22;398(6729):708-13
references.pmid: 10227293
references.citation: Int J Nanomedicine. 2011;6:3011-9
references.pmid: 22162658
references.citation: J Mol Recognit. 2010 Jul-Aug;23(4):343-51
references.pmid: 19941302
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6456-61
references.pmid: 21464285
references.citation: Biophys J. 1997 Apr;72(4):1541-55
references.pmid: 9083660
references.citation: J Mol Recognit. 2007 Jul-Aug;20(4):215-26
references.pmid: 17703463
references.citation: Mol Cell Biol. 2003 Aug;23(16):5540-55
references.pmid: 12897129
references.citation: Nat Struct Mol Biol. 2008 Dec;15(12):1334-42
references.pmid: 19043414
references.citation: Nature. 2000 Mar 2;404(6773):99-103
references.pmid: 10716451
references.citation: Oncogene. 2003 May 22;22(21):3231-42
references.pmid: 12761493
references.citation: Oncogene. 2003 Oct 23;22(48):7607-16
references.pmid: 14576823
references.citation: Nat Rev Cancer. 2002 Aug;2(8):605-15
references.pmid: 12154353
references.citation: Nature. 2000 Oct 5;407(6804):645-8
references.pmid: 11034215
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W407-11
references.pmid: 20525787
references.citation: J Biol Chem. 2000 May 19;275(20):15226-31
references.pmid: 10809758
references.citation: Br J Cancer. 2013 Jun 25;108(12):2495-504
references.pmid: 23736031
references.citation: Cell Death Differ. 2008 Dec;15(12):1941-51
references.pmid: 18806757
references.citation: Science. 1978 May 12;200(4342):618-27
references.pmid: 347575
references.citation: J Biol Chem. 2011 Oct 14;286(41):35388-35395
references.pmid: 21852228
references.citation: Biochem Biophys Res Commun. 2000 Jun 24;273(1):342-6
references.pmid: 10873608
references.citation: Oncogene. 1999 Jul 22;18(29):4171-81
references.pmid: 10435630
references.citation: Trends Genet. 2002 Feb;18(2):90-5
references.pmid: 11818141
references.citation: Mol Biol Rep. 2011 Jan;38(1):229-36
references.pmid: 20333547
references.citation: Oncogene. 2003 Jul 31;22(31):4911-7
references.pmid: 12894234
references.citation: EMBO J. 2005 Feb 23;24(4):836-48
references.pmid: 15678106
references.citation: Cell Microbiol. 2005 Oct;7(10):1418-31
references.pmid: 16153242
references.citation: J Mol Recognit. 2011 Nov-Dec;24(6):1043-55
references.pmid: 22038811
references.citation: J Cell Sci. 2005 Oct 15;118(Pt 20):4785-95
references.pmid: 16219686
references.citation: Mol Cancer Ther. 2009 Oct;8(10):2947-58
references.pmid: 19808975
references.citation: Cell Cycle. 2007 Feb 1;6(3):300-4
references.pmid: 17264676
references.citation: Nature. 2000 Nov 16;408(6810):307-10
references.pmid: 11099028
references.citation: Neoplasia. 2006 Aug;8(8):655-66
references.pmid: 16925948
references.citation: Nat Methods. 2006 May;3(5):347-55
references.pmid: 16628204
references.citation: Cancer Cell. 2008 Jul 8;14(1):10-21
references.pmid: 18598940