title: Transactivation specificity is conserved among p53 family proteins and depends on a response element sequence code.
abstract: Structural and biochemical studies have demonstrated that p73, p63 and p53 recognize DNA with identical amino acids and similar binding affinity. Here, measuring transactivation activity for a large number of response elements (REs) in yeast and human cell lines, we show that p53 family proteins also have overlapping transactivation profiles. We identified mutations at conserved amino acids of loops L1 and L3 in the DNA-binding domain that tune the transactivation potential nearly equally in p73, p63 and p53. For example, the mutant S139F in p73 has higher transactivation potential towards selected REs, enhanced DNA-binding cooperativity in vitro and a flexible loop L1 as seen in the crystal structure of the protein-DNA complex. By studying, how variations in the RE sequence affect transactivation specificity, we discovered a RE-transactivation code that predicts enhanced transactivation; this correlation is stronger for promoters of genes associated with apoptosis.
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO), University of Trento, TN, 38060 Italy, Molecular Mutagenesis and DNA Repair Unit, IRCSS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa 16132, Italy, Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA and Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIEHS, NIH, RTP, NC, 27709, USA.
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.forename: Paola
authors.initials: P
authors.lastname: Monti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisio
authors.forename: H Thien
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Abdul S
authors.initials: AS
authors.lastname: Ethayathulla
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos
authors.forename: Giorgia
authors.initials: G
authors.lastname: Foggetti
authors.forename: Paola
authors.initials: P
authors.lastname: Menichini
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Hector
authors.initials: H
authors.lastname: Viadiu
authors.forename: Gilberto
authors.initials: G
authors.lastname: Fronza
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
mesh_terms: D000483:Alleles; D001483:Base Sequence; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010649:Phenylalanine / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011687:Purines / Q000032:analysis; D011743:Pyrimidines / Q000032:analysis; D020218:Response Elements; D012441:Saccharomyces cerevisiae / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011687:Purines; D011743:Pyrimidines; C000606460:TP73 protein, human; D015534:Trans-Activators; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D010649:Phenylalanine; D004247:DNA
references.citation: Cell Cycle. 2011 Apr 15;10(8):1188-9
references.pmid: 21441779
references.citation: J Biol Chem. 2002 Jan 4;277(1):719-24
references.pmid: 11641404
references.citation: Mol Cell. 2006 Jun 23;22(6):741-753
references.pmid: 16793544
references.citation: PLoS One. 2011;6(6):e20643
references.pmid: 21674059
references.citation: Oncogene. 2007 Nov 15;26(52):7363-70
references.pmid: 17563751
references.citation: Nature. 1992 Mar 19;356(6366):215-21
references.pmid: 1552940
references.citation: Nat Struct Mol Biol. 2010 Apr;17(4):423-9
references.pmid: 20364130
references.citation: Mol Cancer Res. 2011 Nov;9(11):1493-9
references.pmid: 21933903
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references.pmid: 21460441
references.citation: Nat Protoc. 2007;2(11):2728-33
references.pmid: 18007608
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1875-80
references.pmid: 10051562
references.citation: Mol Cancer Res. 2011 Mar;9(3):271-9
references.pmid: 21343334
references.citation: Mol Cell Biol. 2005 Jul;25(14):6077-89
references.pmid: 15988020
references.citation: Mol Cancer Res. 2004 Jul;2(7):371-86
references.pmid: 15280445
references.citation: Cell Death Differ. 2012 Jan;19(1):180-3
references.pmid: 22095277
references.citation: Cell Cycle. 2010 Oct 15;9(20):4068-76
references.pmid: 20948308
references.citation: Cell Cycle. 2007 Feb 1;6(3):262-8
references.pmid: 17224651
references.citation: Carcinogenesis. 1997 Oct;18(10):2019-21
references.pmid: 9364015
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9934-9
references.pmid: 12909720
references.citation: J Nucleic Acids. 2012;2012:687359
references.pmid: 22007292
references.citation: Genes Cancer. 2011 Apr;2(4):475-84
references.pmid: 21779515
references.citation: Oncogene. 2002 Feb 7;21(7):990-9
references.pmid: 11850816
references.citation: Nucleic Acids Res. 2003 Sep 1;31(17):5108-21
references.pmid: 12930962
references.citation: Nature. 1999 Apr 22;398(6729):708-13
references.pmid: 10227293
references.citation: Nucleic Acids Res. 2008 Jun;36(11):3639-54
references.pmid: 18474530
references.citation: Nucleic Acids Res. 2011 Mar;39(5):1919-32
references.pmid: 21071400
references.citation: Nature. 1979 Mar 15;278(5701):261-3
references.pmid: 218111
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: Genes Dev. 2010 May 15;24(10):1022-34
references.pmid: 20478995
references.citation: EMBO J. 2011 Jun 1;30(11):2167-76
references.pmid: 21522129
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6456-61
references.pmid: 21464285
references.citation: Genes Cancer. 2011 Apr;2(4):491-502
references.pmid: 21779517
references.citation: Cell Mol Life Sci. 2004 Apr;61(7-8):822-42
references.pmid: 15095006
references.citation: Nature. 2000 Mar 2;404(6773):99-103
references.pmid: 10716451
references.citation: Science. 1992 May 8;256(5058):827-30
references.pmid: 1589764
references.citation: Mol Cell Biol. 2002 Dec;22(24):8612-25
references.pmid: 12446780
references.citation: Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
references.pmid: 18431400
references.citation: Cold Spring Harb Perspect Biol. 2010 Dec;2(12):a000893
references.pmid: 20463001
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):944-9
references.pmid: 18187580
references.citation: EMBO J. 1994 Nov 15;13(22):5393-400
references.pmid: 7957105
references.citation: Structure. 2010 Feb 10;18(2):246-56
references.pmid: 20159469
references.citation: Oncogene. 2003 Aug 14;22(34):5252-60
references.pmid: 12917626
references.citation: Cell Death Differ. 2010 Jun;17(6):901-11
references.pmid: 20379196
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14994-9
references.pmid: 14630945
references.citation: Oncogene. 2001 Jan 25;20(4):501-13
references.pmid: 11313981
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4930-5
references.pmid: 15037740
references.citation: Science. 1994 Jul 15;265(5170):346-55
references.pmid: 8023157
references.citation: FEBS Lett. 2001 Jan 26;489(1):4-7
references.pmid: 11231003
references.citation: Cell. 1997 Aug 22;90(4):809-19
references.pmid: 9288759
references.citation: Nature. 1999 Apr 22;398(6729):714-8
references.pmid: 10227294
references.citation: Nucleic Acids Res. 2010 Apr;38(7):2256-67
references.pmid: 20064878
references.citation: Eur J Biochem. 2001 May;268(10):2764-72
references.pmid: 11358490
references.citation: Nucleic Acids Res. 2007;35(1):340-52
references.pmid: 17170001
references.citation: J Biol Chem. 2012 Mar 2;287(10):7477-86
references.pmid: 22247550
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):3988-93
references.pmid: 15738397
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Methods Enzymol. 2003;374:300-21
references.pmid: 14696379
references.citation: Oncogene. 2008 Jul 3;27(29):4013-23
references.pmid: 18278067
references.citation: PLoS One. 2010 Apr 21;5(4):e10236
references.pmid: 20422012
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6066-71
references.pmid: 22474346
references.citation: J Biol Chem. 2013 Feb 15;288(7):4744-54
references.pmid: 23243311
references.citation: BMC Genomics. 2009 Dec 23;10:628
references.pmid: 20030809
references.citation: EMBO J. 1999 Aug 16;18(16):4424-37
references.pmid: 10449408
references.citation: Nature. 2002 Apr 4;416(6880):560-4
references.pmid: 11932750
references.citation: PLoS Genet. 2008 Jun 27;4(6):e1000104
references.pmid: 18714371
references.citation: Nucleic Acids Res. 2008 Apr;36(6):1900-12
references.pmid: 18267967
references.citation: Mol Cell Biol. 2006 Mar;26(6):2297-308
references.pmid: 16508005
references.citation: Mol Cell. 2006 Dec 28;24(6):841-51
references.pmid: 17189187
references.citation: J Biol Chem. 2006 Jul 21;281(29):20464-73
references.pmid: 16687402
references.citation: Oncogene. 2009 Jan 22;28(3):325-33
references.pmid: 18978813
references.citation: Oncogene. 2009 Dec 17;28(50):4469-79
references.pmid: 19855428
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14338-42
references.pmid: 9405613
references.citation: Mol Cell. 2010 May 14;38(3):356-68
references.pmid: 20471942
references.citation: Mol Cell. 1998 Sep;2(3):305-16
references.pmid: 9774969
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: J Mol Biol. 2012 Jan 20;415(3):503-13
references.pmid: 22100306
references.citation: J Biol Chem. 2006 Jul 21;281(29):20494-502
references.pmid: 16717092
references.citation: Nat Genet. 1992 Apr;1(1):45-9
references.pmid: 1301998
references.citation: Nat Rev Cancer. 2009 Oct;9(10):724-37
references.pmid: 19776742
references.citation: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references.pmid: 7984417
references.citation: Mol Cell Biol. 2002 Apr;22(8):2575-85
references.pmid: 11909952
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14387-92
references.pmid: 22908277
references.citation: Cell Death Differ. 2012 Dec;19(12):1992-2002
references.pmid: 22790872
references.citation: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8251-6
references.pmid: 21525412