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Oncogenomics Oncogene (2002) 21, 7901 – 7911 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites Hua Qian1,4, Ting Wang1, Louie Naumovski2, Charles D Lopez3 and Rainer K Brachmann*,1,5 1Division of Oncology, Department of Medicine, Washington University School of Medicine, 660 S Euclid Avenue, Box 8069, St Louis, Missouri, MO 63110, USA; 2Division of Hematology, Oncology and Stem Cell Transplantation, Stanford University, 269 Campus Drive, CCSR Room 1215, Stanford, California, CA 94305, USA; 3Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Baird Hall Room 3030, Portland, Oregon, OR 97201, USA The tumor suppressor protein p53, once activated, can and/or apoptosis (Prives and Hall, 1999; Vogelstein et cause either cell cycle arrest or apoptosis through al., 2000). Direct target genes of p53 have one or more transactivation of target genes with p53 DNA binding p53 DNA binding site(s) (DBS) very similar to the p53 sites (DBS). To investigate the role of p53 DBS in the consensus DBS that consists of two copies of the 10 regulation of this profound, yet poorly understood base pair (bp) motif 5’-PuPuPuC(A/T)(T/A)GPyPyPy- decision of life versus death, we systematically studied 3’ separated by 0 – 13 bp (el-Deiry et al., 1992; Funk et all known and potential p53 DBS. We analysed the DBS al., 1992). However, only one p53 DBS, Type IV separated from surrounding promoter regions in yeast Collagenase, is a perfect match for the p53 consensus and mammalian assays with and without DNA damage. DBS. There are over 60 genes with known or potential p53 efficiently utilized the DBS of MDM2 and of genes p53 DBS (see Tables 1 and 2). The biological activities connected to cell cycle arrest, DNA repair and the death of many are consistent with established p53 effects. For receptor pathway of apoptosis. However, p53 was unable example, the p21 and 14-3-3s genes are involved in to utilize two-thirds of the isolated DBS, a subset that p53-mediated G1 and G2 cell cycle arrest, respectively. included almost all DBS of apoptosis-related genes. The GADD45, p53R2 and PCNA genes have roles in Neither ASPP2, a p53-interacting protein reported to DNA repair, and the growing list of apoptosis-related specifically stimulate p53 transcriptional activity on genes includes Bax, Noxa, p53AIP1, PERP and PIG3. apoptosis-related promoters, nor DNA damage resulted Genes that are part of the death receptor pathway of in p53 utilization of isolated DBS of apoptosis-related apoptosis are also represented, such as Fas, KILLER/ genes. Thus, a major regulation of p53 activity occurs at DR5 and Pidd (Bates and Vousden, 1999; Hengartner, the level of p53 DBS themselves by posing additional 2000; Ko and Prives, 1996; Levine, 1997; Prives and requirements for the successful utilization of apoptosis- Hall, 1999; Rich et al., 2000; Sionov and Haupt, 1999; related DBS. Vogelstein et al., 2000; Vousden, 2000). In addition, Oncogene (2002) 21, 7901 – 7911. doi:10.1038/sj.onc. p53 induces MDM2, a target gene that creates a 1205974 negative feedback loop with p53 to maintain low p53 protein levels in unstressed cells (Haupt et al., 1997; Keywords: apoptosis; cell cycle; DNA binding site; Kubbutat et al., 1997; Prives, 1998). The role of many DNA repair; p53 other known or potential target genes in the p53 context remains poorly defined. For example, p53 may drive the transcription of growth-promoting genes, such as c-fos,c-met, Epidermal Growth Factor Receptor Introduction and Transforming Growth Factor-a (Elkeles et al., 1999; Ludes-Meyers et al., 1996; Seol et al., 1999; Shin et al., p53 exerts its tumor suppressor function, in part, as a 1995). ONCOGENOMICS transcription factor that induces effector genes once It is also still unclear why some cells respond to p53 activated by upstream signals, such as DNA damage. activation with cell cycle arrest, while others undergo Activated p53 results in DNA repair, cell cycle arrest apoptosis. Cell type, amount of DNA damage, the presence of survival factors and the inappropriate activity of oncogenes appear to be important, but what *Correspondence: RK Brachmann; E-mail: [email protected] exact underlying mechanisms govern the profound Current addresses: 4Department of Surgery, Xin Hua Hospital, decision of survival versus death after p53 activation Shanghai Second Medical University, 1665 Kong Jiang Road, remains unknown (Bates and Vousden, 1999; Sionov 5 Shanghai, 200092, PR China; Division of Hematology/Oncology, and Haupt, 1999; Vousden, 2000). Several models have Department of Medicine, University of California at Irvine, Medical Sciences I, C250, Irvine, California, CA 92697, USA been put forth. In the ‘p53 dumb’ model, activated p53 Received 22 April 2002; revised 12 August 2002; accepted 13 always leads to the same downstream signals, including August 2002 upregulated cell cycle arrest and apoptotis genes, and p53 and p53 DNA binding sites H Qian et al 7902 Table 1 Sequences of known and potential p53 DNA binding sites The shown sequences are the sequences used in our study. For genes with several p53 DNA binding sites (DBS), we tried to use the terminology of the original papers as much as possible. With a few exceptions, we used the actual p53 DBS plus 5 bp up- and downstream (if the information was available). The p53 consensus DBS (Nat Genet 1, 450) is shown on top (R=A or G; W=A or T; Y=C or T). Our alignment tries as much as possible to take previous alignments into consideration. Bold blue nucleotides in capitals conform to the p53 consensus DBS. Regular blue nucleotides in capitals are additional nucleotides that conform to motifs of the p53 consensus DBS. Bold green nucleotides represent a motif (TGCCT) that was proposed to be important for p53 binding (Science 252, 1708). Both c-fos and MDM2 have two complete p53 DBS, and we have aligned those to each other. References for the p53 DBS sequences can be found in Table 2. these signals are then modulated by other pathways. In genes (Vousden, 2000). ASPP1 and ASPP2 have been the ‘p53 smart’ model, increased p53 protein levels, characterized as p53 coactivators that specifically specific post-translational p53 modifications and/or the stimulate the apoptotic function of p53. They appear recruitment of specific coactivators determine the to do so by enhancing the DNA binding and expression levels of cell cycle arrest and apoptotis transcriptional activity of p53 at apoptosis-related Oncogene p53 and p53 DNA binding sites H Qian et al 7903 Table 2 Phenotypes for 67 p53 yeast assay The phenotypes at 308C and 378C were the same, except where indicated. ‘-’: no growth, ‘+’: minimal growth, ‘++’: moderate growth, ‘+++’: growth similar to p53 consensus DBS. All DBS are of human origin, except where indicated (amouse, brat). The ‘m2’ column indicates the mismatches with the p53 consensus DBS. Bold, shadowed numbers indicate that interspersed sequences between the two half-sites of p53 DBS are present. MDM2 and c-fos have two adjacent p53 DBS and the mismatches of each DBS are shown. Underlined, italic numbers point out the 5 p53 DBS that do not conform to our proposed rules for p53 DBS. References: 1Molecular Cell 1,3;2EMBO J 17, 5015; 3Nat Genet 14, 482; 4EMBO J 13, 4816; 5Oncogene 13, 1965; 6Cell 75, 817; 7Genes Dev 12, 2102; 8Proc Natl Acad Sci U S A 97, 109; 9J Biol Chem 275, 20127; 10J Biol Chem 269, 6383; 11Cell 71, 587; 12Nature 404, 42; 13Proc Natl Acad Sci U S A 93, 895; 14J Biol Chem 275, 3867; 15Oncogene 19, 1735; 16Nat Genet 26, 122; 17Cell 80, 293; 18Oncogene 16, 2177; 19Mol Cell Biol 20, 233; 20Nature 377, 646; 21Mol Cell Biol 20, 5602; 22Science 288, 1053; 23Cell 102, 849; 24Genes Dev 14, 704; 25Nature 389, 300; 26Oncogene 15, 2145; 27Hum Mol Genet 7, 1039; 28Genes Dev 7, 1126; 29Nucleic Acids Res 23, 2584; 30J Biol Chem 273, 15387; 31Oncogene 18, 127; 32Science 252, 1708; 33FEBS Lett 445, 265; 34Mol Cell Biol 17, 6330; 35J Biol Chem 275, 15557; 36Mol Cell Biol 19, 2594; 37J Biol Chem 274, 3565; 38Anticancer Res 16, 105; 39Oncogene 19, 1843; 40J Biol Chem 274, 37679; 41Blood 90, 1373; 42Mol Cell Biol 16, 6009; 43Cancer Res 60, 3722; 44J Biol Chem 274, 12061; 45Nucleic Acids Res 25, 983; 46Nat Med 1, 570; 47Proc Natl Acad Sci U S A 95, 11307; 48Cell Growth Differ 10, 295; 49J Biol Chem 275, 6051; 50Genes Dev 6, 1143; 51FEBS Lett 436, 139; 52Oncogene 16, 2479; 53Cancer Res 57, 3281; 54Nucleic Acids Res 23, 3710; 55J Biol Chem 271, 12414; 56Oncogene 16, 1299; 57Oncogene 18, 7740; 58Mol Cell Biol 15, 4694; 59Gene 193,5;60J Biol Chem 270, 19312; 61Carcinogenesis 17, 2559. p53 DBS for the following genes were published too late for our study: Apaf-1 (Nat Cell Biol 3, 552), APC (J Biol Chem 276, 18193), c-Ha-Ras (Oncogene 19, 5831), Caspase-1 (J Biol Chem 276, 10585), hMSH2 (J Biol Chem 276, 27363), p53DINP1 (Mol Cell 8, 85), PTEN (Mol Cell 8, 317) and PUMA (Mol Cell 7, 673; Mol Cell 7, 683) promoters (Lane, 2001; Samuels-Lev et al., 2001). regulatory mechanisms by providing more or less Thus, the activity of ASPP proteins would fit into the perfect binding sites for p53. Differences between p53 ‘p53 smart’ model (Vousden, 2000). In addition, DBS have been previously noted. For example, p53 genetic approaches in mice and chromatin immuno- cancer mutants were found to have differential DNA precipitation (ChIP) analysis have recently shown that binding properties and transcriptional activities when p53 requires its family members p73 and p63 to be tested with several p53 DBS (Campomenosi et al., present in order to bind to the promoters of and 2001; Di Como and Prives, 1998; Friedlander et al., transactivate apoptosis genes (Flores et al., 2002).
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