The tumor suppressor p53: from structures to drug discovery.

Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.

[1]  G. Wahl,et al.  Targeting Mdm2 and Mdmx in Cancer Therapy: Better Living through Medicinal Chemistry? , 2009, Molecular Cancer Research.

[2]  A. Joachimiak,et al.  Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor. , 2006, Genes & development.

[3]  A. Yang,et al.  On the shoulders of giants: p63, p73 and the rise of p53. , 2002, Trends in genetics : TIG.

[4]  G. Wahl,et al.  Mouse Mutants Reveal that Putative Protein Interaction Sites in the p53 Proline-Rich Domain Are Dispensable for Tumor Suppression , 2006, Molecular and Cellular Biology.

[5]  A. Fersht,et al.  Structural biology of the tumor suppressor p53. , 2008, Annual review of biochemistry.

[6]  E. Pérez-Payá,et al.  Solvent‐exposed residues located in the β‐sheet modulate the stability of the tetramerization domain of p53—A structural and combinatorial approach , 2007, Proteins.

[7]  L. R. Dearth,et al.  Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers. , 2007, Carcinogenesis.

[8]  J. Brownell,et al.  Topors Functions as an E3 Ubiquitin Ligase with Specific E2 Enzymes and Ubiquitinates p53* , 2004, Journal of Biological Chemistry.

[9]  Alan R. Fersht,et al.  Mechanism of folding and assembly of a small tetrameric protein domain from tumor suppressor p53 , 1999, Nature Structural Biology.

[10]  Ronen Marmorstein,et al.  Structure of the p53 Core Domain Dimer Bound to DNA*♦ , 2006, Journal of Biological Chemistry.

[11]  H. Jane Dyson,et al.  Cooperative regulation of p53 by modulation of ternary complex formation with CBP/p300 and HDM2 , 2009, Proceedings of the National Academy of Sciences.

[12]  P. Jeffrey,et al.  Structural differences in the DNA binding domains of human p53 and its C. elegans ortholog Cep-1. , 2004, Structure.

[13]  Y. Cordeiro,et al.  Cognate DNA stabilizes the tumor suppressor p53 and prevents misfolding and aggregation. , 2009, Biochemistry.

[14]  C. Prives,et al.  Mutational Analysis of the p53 Core Domain L1 Loop* , 2006, Journal of Biological Chemistry.

[15]  D. Lane,et al.  Directed evolution of p53 variants with altered DNA-binding specificities by in vitro compartmentalization. , 2007, Journal of molecular biology.

[16]  Alberto Inga,et al.  Novel human p53 mutations that are toxic to yeast can enhance transactivation of specific promoters and reactivate tumor p53 mutants , 2001, Oncogene.

[17]  V. Dötsch,et al.  Structural evolution of C‐terminal domains in the p53 family , 2007, The EMBO journal.

[18]  A. Fersht,et al.  Cooperative binding of tetrameric p53 to DNA. , 2004, Journal of molecular biology.

[19]  M. Babu,et al.  The rules of disorder or why disorder rules. , 2009, Progress in biophysics and molecular biology.

[20]  A. Fersht,et al.  Modulation of the Oligomerization State of p53 by Differential Binding of Proteins of the S100 Family to p53 Monomers and Tetramers♦ , 2009, Journal of Biological Chemistry.

[21]  J. Boeke,et al.  Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations , 1998, The EMBO journal.

[22]  E. Conseiller,et al.  Definition of a p53 transactivation function-deficient mutant and characterization of two independent p53 transactivation subdomains , 1999, Oncogene.

[23]  A. Fersht,et al.  Members of the S100 family bind p53 in two distinct ways , 2008, Protein science : a publication of the Protein Society.

[24]  Donald Bashford,et al.  A fluid salt-bridging cluster and the stabilization of p53. , 2007, Journal of molecular biology.

[25]  Maxwell D Cummings,et al.  Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells. , 2005, Journal of medicinal chemistry.

[26]  T. Holak,et al.  NMR indicates that the small molecule RITA does not block p53-MDM2 binding in vitro , 2005, Nature Medicine.

[27]  A. Fersht,et al.  Structures of p53 Cancer Mutants and Mechanism of Rescue by Second-site Suppressor Mutations* , 2005, Journal of Biological Chemistry.

[28]  T. Holak,et al.  Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain , 2008, Cell cycle.

[29]  Alan R. Fersht,et al.  Solution structure of p53 core domain: Structural basis for its instability , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  S. Benchimol,et al.  TRIMming p53 for ubiquitination , 2009, Proceedings of the National Academy of Sciences.

[31]  M. Grütter,et al.  Crystallization and structure solution of p53 (residues 326-356) by molecular replacement using an NMR model as template. , 1998, Acta crystallographica. Section D, Biological crystallography.

[32]  Su Qiu,et al.  Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction. , 2006, Journal of medicinal chemistry.

[33]  G. Wahl,et al.  A leucine‐rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking , 1999, The EMBO journal.

[34]  Ivo Tews,et al.  Specificity determinants of recruitment peptides bound to phospho-CDK2/cyclin A. , 2002, Biochemistry.

[35]  Jean-Christophe Marine,et al.  Mdmx as an essential regulator of p53 activity. , 2005, Biochemical and biophysical research communications.

[36]  Frank M Boeckler,et al.  Targeted rescue of a destabilized mutant of p53 by an in silico screened drug , 2008, Proceedings of the National Academy of Sciences.

[37]  Jan Bergman,et al.  PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. , 2009, Cancer cell.

[38]  R. Ribeiro,et al.  A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer , 2002, Nature Structural Biology.

[39]  Marc S. Cortese,et al.  Analysis of molecular recognition features (MoRFs). , 2006, Journal of molecular biology.

[40]  D. Parks,et al.  Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo , 2006, Molecular Cancer Therapeutics.

[41]  M. Olivier,et al.  Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database , 2007, Human mutation.

[42]  A. Fersht,et al.  Thermodynamic stability of wild-type and mutant p53 core domain. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Malecka,et al.  Crystal Structure of a p53 Core Tetramer Bound to DNA , 2008, Oncogene.

[44]  Wei Gu,et al.  Modes of p53 Regulation , 2009, Cell.

[45]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[46]  Guillermina Lozano,et al.  Pirh2, a p53-Induced Ubiquitin-Protein Ligase, Promotes p53 Degradation , 2003, Cell.

[47]  K. Kinzler,et al.  Oncogenic forms of p53 inhibit p53-regulated gene expression. , 1992, Science.

[48]  Roberto Sanchez,et al.  Structural mechanism of the bromodomain of the coactivator CBP in p53 transcriptional activation. , 2004, Molecular cell.

[49]  K. Sakaguchi,et al.  Damage-mediated Phosphorylation of Human p53 Threonine 18 through a Cascade Mediated by a Casein 1-like Kinase , 2000, The Journal of Biological Chemistry.

[50]  N. Pavletich,et al.  Structure of the p53 Tumor Suppressor Bound to the Ankyrin and SH3 Domains of 53BP2 , 1996, Science.

[51]  David J Weber,et al.  SOLUTION STRUCTURE OF THE C-TERMINAL NEGATIVE REGULATORY DOMAIN OF P53 IN A COMPLEX WITH CA2+-BOUND S100B(BB) , 2000 .

[52]  Chong Li,et al.  Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX , 2009, Proceedings of the National Academy of Sciences.

[53]  G. Clore,et al.  A systematic case study on using NMR models for molecular replacement: p53 tetramerization domain revisited. , 2000, Acta crystallographica. Section D, Biological crystallography.

[54]  Jun Qin,et al.  ARF-BP1/Mule Is a Critical Mediator of the ARF Tumor Suppressor , 2005, Cell.

[55]  Paul W Brandt-Rauf,et al.  NMR solution structure of a peptide from the mdm-2 binding domain of the p53 protein that is selectively cytotoxic to cancer cells. , 2004, Biochemistry.

[56]  E. Orlova,et al.  The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity , 2006, The EMBO journal.

[57]  Sebastian Mayer,et al.  Effects of Common Cancer Mutations on Stability and DNA Binding of Full-length p53 Compared with Isolated Core Domains* , 2006, Journal of Biological Chemistry.

[58]  A. Fersht,et al.  Kinetic Instability of p53 Core Domain Mutants , 2003, Journal of Biological Chemistry.

[59]  C. Arrowsmith,et al.  Solution structure of the tetrameric minimum transforming domain of p53 , 1995, Nature Structural Biology.

[60]  Xinbin Chen,et al.  Identification of a Novel p53 Functional Domain That Is Necessary for Mediating Apoptosis* , 1998, The Journal of Biological Chemistry.

[61]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[62]  A Keith Dunker,et al.  Characterization of molecular recognition features, MoRFs, and their binding partners. , 2007, Journal of proteome research.

[63]  I. Ellis,et al.  Abstract 313: Regulation of p53 Tetramerization and Nuclear Export by ARC , 2006 .

[64]  Shuichi Tsutsumi,et al.  A global map of p53-binding sites in the human genome , 2007 .

[65]  M. Bolognesi,et al.  Function and Structure of Inherently Disordered Proteins This Review Comes from a Themed Issue on Proteins Edited Prediction of Non-folding Proteins and Regions Frequency of Disordered Regions Protein Evolution Partitioning Unstructured Proteins and Regions into Groups Involvement of Inherently Diso , 2022 .

[66]  R. Kriwacki,et al.  Disruption of an intermonomer salt bridge in the p53 tetramerization domain results in an increased propensity to form amyloid fibrils , 2005, Protein science : a publication of the Protein Society.

[67]  V. Rotter,et al.  Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations. , 2009, Journal of molecular biology.

[68]  M. Geiser,et al.  Crystal Structures of Human MdmX (HdmX) in Complex with p53 Peptide Analogues Reveal Surprising Conformational Changes* , 2009, Journal of Biological Chemistry.

[69]  G. Marius Clore,et al.  Refined solution structure of the oligomerization domain of the tumour suppressor p53 , 1995, Nature Structural Biology.

[70]  T. Jacks,et al.  Restoration of p53 function leads to tumour regression in vivo , 2007, Nature.

[71]  Christopher J. Oldfield,et al.  Intrinsic disorder in transcription factors. , 2006, Biochemistry.

[72]  Sebastian Mayer,et al.  Correlation of levels of folded recombinant p53 in escherichia coli with thermodynamic stability in vitro. , 2007, Journal of molecular biology.

[73]  Galina Selivanova,et al.  Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound , 2002, Nature Medicine.

[74]  Johannes Buchner,et al.  p53 contains large unstructured regions in its native state. , 2002, Journal of molecular biology.

[75]  A. Fersht,et al.  Stabilising the DNA-binding domain of p53 by rational design of its hydrophobic core , 2009, Protein engineering, design & selection : PEDS.

[76]  T. Darden,et al.  p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay , 2001, Oncogene.

[77]  M. Kitayner,et al.  Structural basis of DNA recognition by p53 tetramers. , 2006, Molecular cell.

[78]  D. Livingston,et al.  Binding and modulation of p53 by p300/CBP coactivators , 1997, Nature.

[79]  W. El-Deiry,et al.  CARPs are E3 ligases that target apical caspases and p53 , 2007, Cancer biology & therapy.

[80]  Lee Baker,et al.  Discovery, In Vivo Activity, and Mechanism of Action of a Small-Molecule p53 Activator , 2007, Cancer cell.

[81]  G. Wahl,et al.  Regulating the p53 pathway: in vitro hypotheses, in vivo veritas , 2006, Nature Reviews Cancer.

[82]  K. Wiman,et al.  PRIMA-1MET Inhibits Growth of Mouse Tumors Carrying Mutant p53 , 2008, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[83]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[84]  J. Lukin,et al.  Molecular basis of Pirh2-mediated p53 ubiquitylation , 2008, Nature Structural &Molecular Biology.

[85]  A. Levine,et al.  One billion years of p53/p63/p73 evolution , 2009, Proceedings of the National Academy of Sciences.

[86]  G. Wahl,et al.  Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4 , 2006, Cell Death and Differentiation.

[87]  E. Giralt,et al.  Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand , 2008, Proceedings of the National Academy of Sciences.

[88]  A. Fersht,et al.  Structural basis for understanding oncogenic p53 mutations and designing rescue drugs , 2006, Proceedings of the National Academy of Sciences.

[89]  Deepak Srinivasan,et al.  The electrostatic surface of MDM2 modulates the specificity of its interaction with phosphorylated and unphosphorylated p53 peptides , 2008, Cell cycle.

[90]  A. Fersht,et al.  Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy , 2000, Oncogene.

[91]  C. Arrowsmith,et al.  Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Jesse D. Martinez,et al.  Different mutant/wild-type p53 combinations cause a spectrum of increased invasive potential in nonmalignant immortalized human mammary epithelial cells. , 2008, Neoplasia.

[93]  A. Wlodawer,et al.  Two distinct motifs within the p53 transactivation domain bind to the Taz2 domain of p300 and are differentially affected by phosphorylation. , 2009, Biochemistry.

[94]  Shaomeng Wang,et al.  Reactivation of p53 by a specific MDM2 antagonist (MI-43) leads to p21-mediated cell cycle arrest and selective cell death in colon cancer , 2008, Molecular Cancer Therapeutics.

[95]  C. Prives,et al.  Blinded by the Light: The Growing Complexity of p53 , 2009, Cell.

[96]  A. Gronenborn,et al.  The oligomerization domain of p53: Crystal structure of the trigonal form , 1996, FEBS letters.

[97]  A. Fersht,et al.  Crystal Structure of a Superstable Mutant of Human p53 Core Domain , 2004, Journal of Biological Chemistry.

[98]  A. Fersht,et al.  Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[99]  Andreas Prlic,et al.  SISYPHUS—structural alignments for proteins with non-trivial relationships , 2006, Nucleic Acids Res..

[100]  A. Fersht,et al.  Algorithm for prediction of tumour suppressor p53 affinity for binding sites in DNA , 2008, Nucleic acids research.

[101]  Song Tan,et al.  Crystal structure of the yeast MATα2/MCM1/DNA ternary complex , 1998, Nature.

[102]  M. Olivier,et al.  The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. , 2007, Cancer letters.

[103]  H. Dyson,et al.  Mapping the interactions of the p53 transactivation domain with the KIX domain of CBP. , 2009, Biochemistry.

[104]  Ronen Marmorstein,et al.  Acetylation of the p53 DNA-binding domain regulates apoptosis induction. , 2006, Molecular cell.

[105]  Bei Wang,et al.  Redefining the p53 response element , 2009, Proceedings of the National Academy of Sciences.

[106]  J. Qin,et al.  Negative regulation of the deacetylase SIRT1 by DBC1 , 2008, Nature.

[107]  R. Goodman,et al.  CBP/p300 in cell growth, transformation, and development. , 2000, Genes & development.

[108]  P. Hainaut,et al.  The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy. , 2009, Cancer letters.

[109]  Christopher J. Oldfield,et al.  Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners , 2008, BMC Genomics.

[110]  Dajun Yang,et al.  Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition , 2008, Proceedings of the National Academy of Sciences.

[111]  D. Livingston,et al.  Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. , 2002, Genes & development.

[112]  K. Kinzler,et al.  Definition of a consensus binding site for p53 , 1992, Nature Genetics.

[113]  A. Fersht,et al.  Adaptive evolution of p53 thermodynamic stability. , 2009, Journal of molecular biology.

[114]  A. Fersht,et al.  14-3-3 activation of DNA binding of p53 by enhancing its association into tetramers , 2008, Nucleic acids research.

[115]  Pankaj Oberoi,et al.  Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. , 2005, Cancer cell.

[116]  G. Dubin,et al.  High affinity interaction of the p53 peptide-analogue with human Mdm2 and Mdmx , 2009, Cell cycle.

[117]  A. Fersht,et al.  Structural evolution of p53, p63, and p73: Implication for heterotetramer formation , 2009, Proceedings of the National Academy of Sciences.

[118]  Ying Wang,et al.  Structure of the human p53 core domain in the absence of DNA. , 2007, Acta crystallographica. Section D, Biological crystallography.

[119]  Kyou-Hoon Han,et al.  Local Structural Elements in the Mostly Unstructured Transcriptional Activation Domain of Human p53* , 2000, The Journal of Biological Chemistry.

[120]  A. Fersht,et al.  A peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[121]  Ruth Nussinov,et al.  Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View , 2009, PLoS Comput. Biol..

[122]  A. Fersht,et al.  Quaternary structures of tumor suppressor p53 and a specific p53–DNA complex , 2007, Proceedings of the National Academy of Sciences.

[123]  Patrick Dowd,et al.  The ubiquitin ligase COP1 is a critical negative regulator of p53 , 2004, Nature.

[124]  J. Butler,et al.  Kinetic partitioning during folding of the p53 DNA binding domain. , 2005, Journal of molecular biology.

[125]  J. Shay,et al.  A transcriptionally active DNA-binding site for human p53 protein complexes , 1992, Molecular and cellular biology.

[126]  Maria Miller,et al.  Structural basis for p300 Taz2-p53 TAD1 binding and modulation by phosphorylation. , 2009, Structure.

[127]  A. Fersht,et al.  Nine hydrophobic side chains are key determinants of the thermodynamic stability and oligomerization status of tumour suppressor p53 tetramerization domain , 1998, The EMBO journal.

[128]  P. Jeffrey,et al.  Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. , 1994, Science.

[129]  A. Fersht,et al.  Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain , 2008, Proceedings of the National Academy of Sciences.

[130]  S. Lowe,et al.  Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas , 2011, Nature.

[131]  M. Protopopova,et al.  Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors , 2004, Nature Medicine.

[132]  A. Fersht,et al.  Semirational design of active tumor suppressor p53 DNA binding domain with enhanced stability. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[133]  Junjie Chen,et al.  DBC1 is a negative regulator of SIRT1 , 2008, Nature.

[134]  Patrick W. Lee,et al.  Biogenesis of p53 Involves Cotranslational Dimerization of Monomers and Posttranslational Dimerization of Dimers , 2002, The Journal of Biological Chemistry.

[135]  Jef D. Boeke,et al.  Structure of a Sir2 enzyme bound to an acetylated p53 peptide. , 2002, Molecular cell.

[136]  C. Klein,et al.  p53--a natural cancer killer: structural insights and therapeutic concepts. , 2006, Angewandte Chemie.

[137]  T. Davison,et al.  p73 and p63 Are Homotetramers Capable of Weak Heterotypic Interactions with Each Other but Not with p53* , 1999, The Journal of Biological Chemistry.

[138]  L. Serpell,et al.  Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor , 2002, The EMBO journal.

[139]  R. Iggo,et al.  Increased apoptosis induction by 121F mutant p53 , 1999, EMBO Journal.

[140]  A. Fersht,et al.  Molecular mechanism of the interaction between MDM2 and p53. , 2002, Journal of molecular biology.

[141]  R. Poon,et al.  How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer? , 2004, Molecular and Cellular Biology.

[142]  A. Fersht,et al.  Four domains of p300 each bind tightly to a sequence spanning both transactivation subdomains of p53 , 2007, Proceedings of the National Academy of Sciences.

[143]  R. Tjian,et al.  p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. , 1995, Science.

[144]  S. Knapp,et al.  Conformational stability and activity of p73 require a second helix in the tetramerization domain , 2009, Cell Death and Differentiation.

[145]  Yi Tang,et al.  Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. , 2006, Molecular cell.

[146]  D. Vaux,et al.  Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans , 2008, Cell Death and Differentiation.

[147]  C. Prives,et al.  Human tumor-derived p53 proteins exhibit binding site selectivity and temperature sensitivity for transactivation in a yeast-based assay , 1998, Oncogene.

[148]  A. Fersht,et al.  Regulation by phosphorylation of the relative affinities of the N-terminal transactivation domains of p53 for p300 domains and Mdm2 , 2009, Oncogene.

[149]  A. Fersht,et al.  Ultraslow oligomerization equilibria of p53 and its implications , 2009, Proceedings of the National Academy of Sciences.

[150]  Toshiaki Hara,et al.  Structure of the Tfb1/p53 complex: Insights into the interaction between the p62/Tfb1 subunit of TFIIH and the activation domain of p53. , 2006, Molecular cell.

[151]  J. Qin,et al.  Trim24 targets endogenous p53 for degradation , 2009, Proceedings of the National Academy of Sciences.

[152]  P. Dong,et al.  p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells , 2007, Clinical & Experimental Metastasis.

[153]  Michael A. Dyer,et al.  MDMX: from bench to bedside , 2007, Journal of Cell Science.

[154]  A. Fersht,et al.  Structure–function–rescue: the diverse nature of common p53 cancer mutants , 2007, Oncogene.

[155]  N. Pavletich,et al.  Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms , 1995, Science.

[156]  D. Bell,et al.  Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53 , 2008, PLoS genetics.