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  • Analysis
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Transcriptional control of human p53-regulated genes

Nature Reviews Molecular Cell Biology volume 9, pages 402–412 (2008)Cite this article

Key Points

  • The p53 pathway responds to various cellular stress signals by triggering the p53 protein, which mediates the transcriptional activation or repression of a host of target genes.

  • We present and analyse a database of 160 experimentally validated p53-binding sites that regulate 122 genes in the human genome and 1 human-born virus.

  • Profile hidden Markov models are presented to better capture the statistical characteristics of p53-binding sites compared with position-specific score matrices (weight matrices).

  • Only ∼50% of the experimentally validated p53-binding sites are in the 5′ promoter-enhancer region of a gene. The remainder are found in exonic and intronic regions.

  • Low-affinity p53-binding sites that poorly match the p53-binding site consensus exist only in a tight 'band' around the transcription start site (TSS) of a gene. A dynamic-acceptance threshold, which depends on the putative site distance from the TSS, can be used to reduce the false-positive rate during p53-site searches.

  • p53-activator sites have a strikingly different distribution of spacer lengths compared with repressor sites. Most importantly, repressor sites do not show a great preference for 0-base-pair spacers.

  • p53-repressor sites that regulate non-apoptosis genes have no preference for 0-base-pair spacers, whereas ∼50% of all known p53-binding sites have 0-base-pair spacers.

Abstract

The p53 protein regulates the transcription of many different genes in response to a wide variety of stress signals. Following DNA damage, p53 regulates key processes, including DNA repair, cell-cycle arrest, senescence and apoptosis, in order to suppress cancer. This Analysis article provides an overview of the current knowledge of p53-regulated genes in these pathways and others, and the mechanisms of their regulation. In addition, we present the most comprehensive list so far of human p53-regulated genes and their experimentally validated, functional binding sites that confer p53 regulation.

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Figure 1: Mechanisms of p53 activation and regulation of downstream targets.
Figure 2: The p53-PHMM binding site motif.
Figure 3: Histograms of spacer lengths by regulation types.
Figure 4: Histogram of p53-binding sites by gene region.
Figure 5: Box plots of normalized affinity scores by 10-kilobase-pair block distances from the transcriptional start site.
Figure 6: Histogram of spacer lengths by regulation type and gene-target function.

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References

  1. Zhao, R. et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14, 981–993 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Feng, Z. et al. The regulation of AMPK β1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1–AKT–mTOR pathways. Cancer Res. 67, 3043–3053 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Funk, W. D., Pak, D. T., Karas, R. H., Wright, W. E. & Shay, J. W. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol. Cell. Biol. 12, 2866–2871 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. el Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992). This paper presents the head-to-head p53-binding motif and the analysis that led to it.

    Article  CAS  PubMed  Google Scholar 

  5. Kern, S. E. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–830 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Bourdon, J. C. et al. Further characterisation of the p53 responsive element — identification of new candidate genes for trans-activation by p53. Oncogene 14, 85–94 (1997). This paper combines experimental and computational methods to explore new p53 targets. It also discusses the importance of clusters of p53 half-sites in the regulatory expression of target genes.

    Article  CAS  PubMed  Google Scholar 

  7. Tan, T. & Chu, G. p53 binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. Mol. Cell. Biol. 22, 3247–3254 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. el Deiry, W. S. et al. Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 55, 2910–2919 (1995).

    CAS  PubMed  Google Scholar 

  9. Espinosa, J. M. & Emerson, B. M. Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. Mol. Cell 8, 57–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Saramäki, A., Banwell, C. M., Campbell, M. J. & Carlberg, C. Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res. 34, 543–554 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000). This review presents the p53 regulatory network, response mechanisms to cell stress and the pathways that suppress cancer occurrence and growth.

    Article  CAS  PubMed  Google Scholar 

  12. Levine, A. J., Hu, W. & Feng, Z. The p53 pathway: what questions remain to be explored? Cell Death Differ. 13, 1027–1036 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997). This review presents the p53 regulatory network and how it functions to reduce the occurrence and how it suppresses the growth of cancer.

    Article  CAS  PubMed  Google Scholar 

  14. Manfredi, J. J. p53 and apoptosis: it's not just in the nucleus anymore. Mol. Cell 11, 552–554 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Rollwagen, F. M., Yu, Z. Y., Li, Y. Y. & Pacheco, N. D. IL-6 rescues enterocytes from hemorrhage induced apoptosis in vivo and in vitro by a bcl-2 mediated mechanism. Clin. Immunol. Immunopathol. 89, 205–213 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Yonish-Rouach, E. et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352, 345–347 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Yang, G. et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl Acad. Sci. USA 103, 16472–16477 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Harris, S. L. & Levine, A. J. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005). This paper presents how feedback loops are a common motif in the regulatory pathways involving p53.

    Article  CAS  PubMed  Google Scholar 

  19. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yu, X., Harris, S. L. & Levine, A. J. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 66, 4795–4801 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Clemens, M. J. Targets and mechanisms for the regulation of translation in malignant transformation. Oncogene 23, 3180–3188 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Elela, S. A. & Nazar, R. N. The ribosomal 5.8S RNA as a target site for p53 protein in cell differentiation and oncogenesis. Cancer Lett. 117, 23–28 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Prats, A.-C. & Prats, H. Translational control of gene expression: role of IRESs and consequences for cell transformation and angiogenesis. Prog. Nucleic Acid Res. Mol. Biol. 72, 367–413 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Yin, X., Fontoura, B. M. A., Morimoto, T. & Carroll, R. B. Cytoplasmic complex of p53 and eEF2. J. Cell Physiol. 196, 474–482 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Zhang, Y. et al. Repression of hsp90 β gene by p53 in UV irradiation-induced apoptosis of Jurkat cells. J. Biol. Chem. 279, 42545–42551 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Agoff, S. N., Hou, J., Linzer, D. I. & Wu, B. Regulation of the human hsp70 promoter by p53. Science 259, 84–87 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Morris, G. F., Bischoff, J. R. & Mathews, M. B. Transcriptional activation of the human proliferating-cell nuclear antigen promoter by p53. Proc. Natl Acad. Sci. USA 93, 895–899 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tanaka, H. et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404, 42–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Smith, M. L. et al. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266, 1376–1380 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Feng, Z. et al. p53 tumor suppressor protein regulates the levels of huntingtin gene expression. Oncogene 25, 1–7 (2006).

    Article  PubMed  CAS  Google Scholar 

  31. Hu, W., Feng, Z., Teresky, A. & Levine, A. J. p53 regulates maternal reproduction through LIF. Nature 450, 721–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Farmer, G., Colgan, J., Nakatani, Y., Manley, J. L. & Prives, C. Functional interaction between p53, the TATA-binding protein (TBP), and TBP-associated factors in vivo . Mol. Cell. Biol. 16, 4295–4304 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Thut, C. J., Chen, J. L., Klemm, R. & Tjian, R. p53 transcriptional activation mediated by coactivators TAFII40 and TAFII60. Science 267, 100–104 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Gu, W., Shi, X. L. & Roeder, R. G. Synergistic activation of transcription by CBP and p53. Nature 387, 819–823 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Lee, K. C., Crowe, A. J. & Barton, M. C. p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding. Mol. Cell. Biol. 19, 1279–1288 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Budhram-Mahadeo, V. et al. p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J. Biol. Chem. 274, 15237–15244 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Ori, A. et al. p53 binds and represses the HBV enhancer: an adjacent enhancer element can reverse the transcription effect of p53. EMBO J. 17, 544–553 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Agostino, S. D. et al. Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 10, 191–202 (2006).

    Article  PubMed  CAS  Google Scholar 

  40. Basile, V., Mantovani, R. & Imbriano, C. DNA damage promotes histone deacetylase 4 nuclear localization and repression of G2/M promoters, via p53 C-terminal lysines. J. Biol. Chem. 281, 2347–2357 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Ceribelli, M., Alcalay, M., Viganò, M. A. & Mantovani, R. Repression of new p53 targets revealed by ChIP on chip experiments. Cell Cycle 5, 1102–1110 (2006). This paper presents experiments that show direct p53-mediated repression through p53-mediated inactivation (squelching) of NF-Y.

    Article  CAS  PubMed  Google Scholar 

  42. Chae, H. D., Yun, J. & Shi, D. Y. Transcription repression of a CCAAT-binding transcription factor CBF/HSP70 by p53. Exp. Mol. Med. 37, 488–491 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Imbriano, C. et al. Direct p53 transcriptional repression: in vivo analysis of CCAAT-containing G2/M promoters. Mol. Cell. Biol. 25, 3737–3751 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yun, J. et al. p53 negatively regulates cdc2 transcription via the CCAAT-binding NF-Y transcription factor. J. Biol. Chem. 274, 29677–29682 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Jung, M. S. et al. p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor. Oncogene 20, 5818–5825 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Matsui, T. et al. Negative regulation of Chk2 expression by p53 is dependent on the CCAAT-binding transcription factor NF-Y. J. Biol. Chem. 279, 25093–25100 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Iotsova, V. & Stehelin, D. Down-regulation of fibronectin gene expression by the p53 tumor suppressor protein. Cell Growth Differ. 7, 629–634 (1996).

    CAS  PubMed  Google Scholar 

  48. Subbaramaiah, K. et al. Inhibition of cyclooxygenase-2 gene expression by p53. J. Biol. Chem. 274, 10911–10915 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Innocente, S. A. & Lee, J. M. p53 is a NF-Y- and p21-independent, Sp1-dependent repressor of cyclin B1 transcription. FEBS Lett. 579, 1001–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Kanaya, T. et al. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin. Cancer Res. 6, 1239–1247 (2000).

    CAS  PubMed  Google Scholar 

  51. Ohlsson, C., Kley, N., Werner, H. & LeRoith, D. p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. Endocrinology 139, 1101–1107 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Kubicka, S. et al. p53 represses CAAT enhancer-binding protein (C/EBP)-dependent transcription of the albumin gene. A molecular mechanism involved in viral liver infection with implications for hepatocarcinogenesis. J. Biol. Chem. 274, 32137–32144 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Sun, Y., Zeng, X.-R., Wenger, L., Firestein, G. S. & Cheung, H. S. P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex. J. Cell. Biochem. 92, 258–269 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Seto, E. et al. Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc. Natl Acad. Sci. USA 89, 12028–12032 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Truant, R., Xiao, H., Ingles, C. J. & Greenblatt, J. Direct interaction between the transcriptional activation domain of human p53 and the TATA box-binding protein. J. Biol. Chem. 268, 2284–2287 (1993).

    CAS  PubMed  Google Scholar 

  56. Farmer, G., Friedlander, P., Colgan, J., Manley, J. L. & Prives, C. Transcriptional repression by p53 involves molecular interactions distinct from those with the TATA box binding protein. Nucleic Acids Res. 24, 4281–4288 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Harms, K. L. & Chen, X. Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res. 67, 3145–3152 (2007). This paper shows that HDAC2 represses p53-mediated regulation of genes by reducing the acetylation of Lys residues in the p53 protein.

    Article  CAS  PubMed  Google Scholar 

  59. Löhr, K., Möritz, C., Contente, A. & Dobbelstein, M. p21/CDKN1A mediates negative regulation of transcription by p53. J. Biol. Chem. 278, 32507–32516 (2003). This paper presents evidence that many genes are indirectly repressed by p53 through p53-mediated induction of CDKN1A (p21 ).

    Article  PubMed  CAS  Google Scholar 

  60. Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J. & Murphy, M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247–3257 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Johnson, R. A., Ince, T. A. & Scotto, K. W. Transcriptional repression by p53 through direct binding to a novel DNA element. J. Biol. Chem. 276, 27716–27720 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Bist, A., Fielding, C. J. & Fielding, P. E. p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. Biochemistry 39, 1966–1972 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Vousden, K. H. Activation of the p53 tumor suppressor protein. Biochim. Biophys. Acta 1602, 47–59 (2002).

    CAS  PubMed  Google Scholar 

  64. Luo, J. et al. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo . Proc. Natl Acad. Sci. USA 101, 2259–2264 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gu, W., Luo, J., Brooks, C. L., Nikolaev, A. Y. & Li, M. Dynamics of the p53 acetylation pathway. Novartis Found. Symp. 259, 197–205 (2004).

    CAS  PubMed  Google Scholar 

  66. Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Barlev, N. A. et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol. Cell 8, 1243–1254 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. McKinney, K. & Prives, C. Efficient specific DNA binding by p53 requires both its central and C-terminal domains as revealed by studies with high-mobility group 1 protein. Mol. Cell. Biol. 22, 6797–6808 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Weinberg, R. L., Veprintsev, D. B., Bycroft, M. & Fersht, A. R. Comparative binding of p53 to its promoter and DNA recognition elements. J. Mol. Biol. 348, 589–596 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Oda, K. et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Jaiswal, A. S. & Narayan, S. p53-dependent transcriptional regulation of the APC promoter in colon cancer cells treated with DNA alkylating agents. J. Biol. Chem. 276, 18193–18199 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38–51 (2006).

    Article  CAS  Google Scholar 

  73. Halazonetis, T. D., Davis, L. J. & Kandil, A. N. Wild-type p53 adopts a 'mutant'-like conformation when bound to DNA. EMBO J. 12, 1021–1028 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Osada, M. et al. Differential recognition of response elements determines target gene specificity for p53 and p63. Mol. Cell. Biol. 25, 6077–6089 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor–DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Inga, A., Storici, F., Darden, T. A. & Resnick, M. A. Differential transactivation by the p53 transcription factor is highly dependent on p53 level and promoter target sequence. Mol. Cell. Biol. 22, 8612–8625 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Balagurumoorthy, P., Lindsay, S. M. & Harrington, R. E. Atomic force microscopy reveals kinks in the p53 response element DNA. Biophys. Chem. 101–102, 611–623 (2002).

    Article  PubMed  Google Scholar 

  78. Olson, W. K., Gorin, A. A., Lu, X. J., Hock, L. M. & Zhurkin, V. B. DNA sequence-dependent deformability deduced from protein–DNA crystal complexes. Proc. Natl Acad. Sci. USA 95, 11163–11168 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wu, M. et al. AMID is a p53-inducible gene downregulated in tumors. Oncogene 23, 6815–6819 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Contente, A., Dittmer, A., Koch, M. C., Roth, J. & Dobbelstein, M. A polymorphic microsatellite that mediates induction of PIG3 by p53. Nature Genet. 30, 315–320 (2002).

    Article  PubMed  Google Scholar 

  81. Thornborrow, E. C., Patel, S., Mastropietro, A. E., Schwartzfarb, E. M. & Manfredi, J. J. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene 21, 990–999 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Koutsodontis, G., Vasilaki, E., Chou, W.-C., Papakosta, P. & Kardassis, D. Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. Biochem. J. 389, 443–455 (2005). This paper presents experiments that confirm that cofactor-binding sites adjacent to p53-binding sites can be crucial in conferring p53-mediated regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Thornborrow, E. C. & Manfredi, J. J. The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter. J. Biol. Chem. 276, 15598–15608 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Cook, J. L. et al. Distance constraints and stereospecific alignment requirements characteristic of p53 DNA-binding consensus sequence homologies. Oncogene 11, 723–733 (1995).

    CAS  PubMed  Google Scholar 

  85. Stenger, J. E. et al. p53 oligomerization and DNA looping are linked with transcriptional activation. EMBO J. 13, 6011–6020 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bond, G. L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Burns, T. F., Fei, P., Scata, K. A., Dicker, D. T. & El-Deiry, W. S. Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells. Mol. Cell. Biol. 23, 5556–5571 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang, Y., Schwedes, J. F., Parks, D., Mann, K. & Tegtmeyer, P. Interaction of p53 with its consensus DNA-binding site. Mol. Cell. Biol. 15, 2157–2165 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Tokino, T. et al. p53 tagged sites from human genomic DNA. Hum. Mol. Genet. 3, 1537–1542 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Flores, E. R. et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416, 560–564 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Wei, C.-L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Hoh, J. et al. The p53MH algorithm and its application in detecting p53-responsive genes. Proc. Natl Acad. Sci. USA 99, 8467–8472 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Barash, Y., Elidan, G., Friedman, N. & Kaplan, T. in RECOMB '03: Proceedings of the Seventh Annual International Conference on Research in Computational Molecular Biology 28–37 (ACM Press, New York, USA, 2003).

    Book  Google Scholar 

  94. Djordjevic, M., Sengupta, A. M. & Shraiman, B. I. A biophysical approach to transcription factor binding site discovery. Genome Res. 13, 2381–2390 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Stormo, G. & Fields, D. Specificity, free energy and information content in protein–DNA interactions. Trends Biochem. Sci. 23, 109–113 (1998).. This paper presents the theory and applicability of position-specific score matrices.

    Article  CAS  PubMed  Google Scholar 

  96. Tompa, M. et al. Assessing computational tools for the discovery of transcription factor binding sites. Nature Biotechnol. 23, 137–144 (2005).

    Article  CAS  Google Scholar 

  97. Wasserman, W. W. & Sandelin, A. Applied bioinformatics for the identification of regulatory elements. Nature Rev. Genet. 5, 276–287 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Yeo, G. & Burge, C. B. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J. Comput. Biol. 11, 377–394 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Krogh, A., Brown, M., Mian, I. S., Sjölander, K. & Haussler, D. Hidden Markov models in computational biology. Applications to protein modeling. J. Mol. Biol. 235, 1501–1531 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Eddy, S. R. Profile hidden Markov models. Bioinformatics 14, 755–763 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Durbin, R., Eddy, S., Krogh, A. & Mitchison, G. Biological Sequence Analysis 1st Edn (Cambridge Univ. Press, 1998). This book provides an excellent introduction to computational methods used to analyse biological sequence data (DNA, RNA and proteins).

    Book  Google Scholar 

  102. Stormo, G. D. DNA binding sites: representation and discovery. Bioinformatics 16, 16–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Schneider, T. D. & Stephens, R. M. Sequence logos: a new way to display consensus sequences. Nucleic Acids Res. 18, 6097–6100 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to apologize to all those researchers whose studies have not been cited because of space limitations. We thank G. Bond, M. Krasnitz, J. Vanicek, R. Rabadan, G. Atwal and A. Vazquez for helpful discussions.

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Authors and Affiliations

  1. The Institute for Advanced Study, Princeton, New Jersey, USA

    Todd Riley, Patricia Chen & Arnold Levine

  2. The BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, New Jersey, USA

    Todd Riley & Eduardo Sontag

  3. The Mathematics Department, Rutgers University, Piscataway, New Jersey, USA

    Eduardo Sontag

  4. The Cancer Institute of New Jersey, New Brunswick, New Jersey, USA

    Arnold Levine

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  1. Todd Riley
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p53HMM algorithm

Glossary

Response element

A short sequence of DNA in or near a gene that can bind one or more transcription factors that can regulate the transcriptional activity of that gene.

Extracellular matrix

The complex, multi-molecular material that surrounds cells. It comprises a scaffold on which tissues are organized, provides cellular microenvironments and regulates various cellular functions.

Ubiquitin ligase

An enzyme that couples the small protein ubiquitin to Lys residues on a target protein, marking that protein for destruction by the 26S proteasome.

Polyubiquitylation

A process whereby a ubiquitin ligase protein attaches multiple ubiquitin molecules, one after the other, to a single Lys residue and thereby marks the protein for degradation by the 26S proteasome.

Senescence

An almost irreversible stage of permanent G1 cell-cycle arrest that is linked to morphological changes (flattening of the cells), metabolic changes and changes in gene expression (for example, β-galactosidase).

Autophagy

A pathway for the recycling of cellular contents, through which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover.

Endosome

A vesicle formed by invagination of the plasma membrane.

Exosome

A membrane vesicle that is secreted into the extracellular milieu as a consequence of multivesicular-body fusion with the plasma membrane.

Protein methylation

A type of post-translational modification, mediated by enzymes, whereby a hydrogen atom is replaced with a methyl group, typically on an Arg or Lys amino-acid residue in the protein sequence.

Protein acetylation

A type of post-translational modification, mediated by enzymes, whereby a hydrogen atom is replaced with an acetyl group.

LINE element

A long interspersed sequence that contains a promoter region, untranslated region and one or more open reading frames, and is generated by retrotransposition.

Profile hidden Markov model

(PHMM). A model that is designed to capture the statistical characteristics of biological sequence data (DNA, RNA or protein). All PHMMs typically have three hidden states (match, insertion and deletion) per nucleotide or amino-acid position.

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Riley, T., Sontag, E., Chen, P. et al. Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9, 402–412 (2008). https://doi.org/10.1038/nrm2395

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