Molecular and Cellular Biochemistry

, Volume 379, Issue 1–2, pp 213–227 | Cite as

Restoration of wild-type p53 in drug-resistant mouse breast cancer cells leads to differential gene expression, but is not sufficient to overcome the malignant phenotype

Article

Abstract

We established a breast cancer cell line from a fast growing mouse WAP-SVT/t breast tumor. Cells from this line, SVTneg2, switched off T-antigen expression, carry a missense mutation at the p53 codon 242 (mouse G242 corresponds to human hot spot mutation G245), are malignantly transformed, highly aneuploid and very insensitive to apoptotic stimuli. To examine the influence of wild-type p53 (wtp53) restoration on the behavior of the SVTneg2 cells, we transfected these cells with wtp53 and generated three permanent cell lines expressing wtp53. Interestingly, restoration of p53 had no influence on chemotherapy sensitivity and the transformation capacity of these breast cancer cells, but markedly changed the gene expression of wtp53-dependent genes after doxorubicin treatment. We postulate that restoration of p53 leads to massive changes in gene expression and to a reduced proliferation rate, but is not sufficient to overcome the malignant phenotype and the chemoresistance of SVTneg2.

Keywords

Trp53 p53 restoration Aneuploidy Chemoresistance Breast cancer 

Notes

Acknowledgments

We acknowledge Bianca Berg for technical assistance. We thank Roland Bell for editing the English version of this manuscript.

Supplementary material

11010_2013_1643_MOESM1_ESM.pptx (99 kb)
Supplementary Fig. 1 Gene expression profile of two differentially regulated genes. The figure shows examples of the expression profile of E2f1 and Cdk1 in the mammary gland epithelial cells of three normal mice, five SVT/t breast cancer and two breast cancer derived cell lines (SVTpos1 and SVTneg2). The expression values are shown in arbitrary units (AU). RNA was isolated from mammary gland tissue from three normal NMRI mice, five WAP-SVT/t breast cancers and two breast cancer derived cell lines (SVTpos1 and SVTneg2) in accordance with the manufacturer’s protocol (RNAzol PeQLab, Biotechnology GmbH). RNA was then hybridized to Affymetrix’s Mouse Expression Set 430A and scanned with the GeneChip Scanner 3000. Further analyses were performed with CorrXpression [79] (PPTX 99 kb)
11010_2013_1643_MOESM2_ESM.pptx (5.2 mb)
Supplementary Fig. 2 SA-β-gal staining under standard conditions for SVTneg2* (a) and SVTneg2·p53cl.7 (b) (magnification ×100), after 48 h treatment with 1 μM doxorubicin for SVTneg2* (c) and (e) (magnification ×40 and ×100) and for SVTneg2·p53cl.13 (d) and (f) (magnification ×40 and ×100); (g) SA-b-Gal positive cells for SVTneg2* and SVTneg2·p53 cells after 48 h doxorubicin incubation were quantified and expressed as % of total cell numbers. Error bars indicate the mean ± SD of three independent staining (PPTX 5281 kb)
11010_2013_1643_MOESM3_ESM.pptx (86 kb)
Supplementary Fig. 3 Wt-p53 restoration leads to a reduced proliferation rate, but is not sufficient to overcome chemoresistance. (A) Flow cytometry analysis of Annexin-V-FITC-labeled SVTneg2* and SVTneg2·p53 cells after 24, 48 and 72 h doxorubicin treatment. The graph shows the  % of Annexin-V positive cells. (B) BrdU proliferation assay. SVTneg2* and SVTneg2·p53 cells were incubated with and without doxorubicin and BrdU labeled. (C) Long term survival assessment by soft agar assays with or without the addition of 0.5 μM doxorubicin. The diagram exhibits the relative colony growth in ± doxorubicin treated cells. Error bars indicate the mean ± SD of three (BrdU and Flow cytometry) or two (Soft agar) independent experiments (PPTX 87 kb)
11010_2013_1643_MOESM4_ESM.pptx (235 kb)
Supplementary Fig. 4 Relative gene expression of Mdm2, Puma (Bbc3), Assp1 and Aspp2 under standard culture conditions and doxorubicin treatment. Mdm2 gene expression was almost comparable in all SVTneg2 cell lines with or without doxorubicin treatment. Puma gene expression remained unchanged after wtp53 restoration under standard culture conditions, but differed significantly under doxorubicin treatment. Gene expression of Aspp1 and Assp2 was affected by wtp53 restoration. Aspp1 and Assp2 expression increased slightly in SVTneg2·p53 cells under standard culture conditions and as well as for Aspp1 under doxorubicin treatment. However, under doxorubicin treatment, Aspp2 gene expression was markedly increased in SVTneg2·p53 cells and remained unchanged in SVTneg2* cells (PPTX 236 kb)
11010_2013_1643_MOESM5_ESM.pptx (202 kb)
Supplementary Fig. 5 Semiquantitative RT–PCR analysis. Total RNA was extracted and reverse transcribed into cDNA. Semiquantitative PCR was performed for Gapdh, p53, p21, Mdm2, Mdm4; p16/19, Cyclin G1 (Ccng1), Enigma (Pdlim7) and Hoxa5. Cell cycle numbers and the size of the expected PCR products are indicated. The complete primer list is presented in Supplementary Table 1 (PPTX 202 kb)
11010_2013_1643_MOESM6_ESM.docx (18 kb)
Supplementary Table 1 Primers were designed with the help of MacMolly Tetra and Primer-Blast. For Enigma, Mmd2 and Mdm4 primer sequences were taken from previous studies [23, 77, 78] (DOCX 19 kb)

References

  1. 1.
    DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ (1979) Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc Natl Acad Sci U S A 76:2420–2424PubMedCrossRefGoogle Scholar
  2. 2.
    Lane DP, Crawford LV (1979) T antigen is bound to a host protein in SV40-transformed cells. Nature 278:261–263PubMedCrossRefGoogle Scholar
  3. 3.
    Linzer DI, Levine AJ (1979) Characterization of a 54 K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell 17:43–52PubMedCrossRefGoogle Scholar
  4. 4.
    Nigro J, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K, Bigner SH, Davidson N, Baylin S, Devilee P (1989) Mutation in the p53 gene occur in diverse human tumour types. Nature 342:705–708PubMedCrossRefGoogle Scholar
  5. 5.
    Lane DP (1992) Cancer p53, guardian of the genome. Nature 358:15–16PubMedCrossRefGoogle Scholar
  6. 6.
    Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331PubMedCrossRefGoogle Scholar
  7. 7.
    Gasco M, Shami S, Crook T (2002) The p53 pathway in breast cancer. Breast Cancer Res 4:70–76PubMedCrossRefGoogle Scholar
  8. 8.
    Bai L, Zhu WG (2006) p53: structure, function and therapeutic applications. J Cancer Mol 2:141–153Google Scholar
  9. 9.
    Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346–355PubMedCrossRefGoogle Scholar
  10. 10.
    Nakamura Y (2004) Isolation of p53-target genes and their functional analysis. Cancer Sci 95:7–11PubMedCrossRefGoogle Scholar
  11. 11.
    Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9:402–412PubMedCrossRefGoogle Scholar
  12. 12.
    McVean M, Xiao H, Isobe K, Pelling JC (2000) Increase in wild-type p53 stability and transactivational activity by the chemopreventive agent apigenin in keratinocytes. Carcinogenesis 21:633–639PubMedCrossRefGoogle Scholar
  13. 13.
    Ju J, Schmitz JC, Song B, Kudo K, Chu E (2007) Regulation of p53 expression in response to 5-fluorouracil in human cancer RKO cells. Clin Cancer Res 13:4245–4251PubMedCrossRefGoogle Scholar
  14. 14.
    Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245PubMedCrossRefGoogle Scholar
  15. 15.
    Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25–27PubMedCrossRefGoogle Scholar
  16. 16.
    Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–1679PubMedCrossRefGoogle Scholar
  17. 17.
    Buschmann T, Adler V, Matusevich E, Fuchs SY, Ronai Z (2000) p53 phosphorylation and association with murine double minute 2, c-Jun NH2-terminal kinase, p14ARF, and p3000/CBP during the cell cycle and after exposure to ultraviolet irradiation. Cancer Res 90:896–900Google Scholar
  18. 18.
    Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278:12207–12213PubMedCrossRefGoogle Scholar
  19. 19.
    Sherr CJ (1998) Tumor surveillance via the ARF-p53 pathway. Genes Dev 12:2984–2991PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathway. Cell 92:725–734PubMedCrossRefGoogle Scholar
  21. 21.
    Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92:713–723PubMedCrossRefGoogle Scholar
  22. 22.
    Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, van Ham RC, van der Houven van Oordt W, Hateboer G, van der Eb AJ (1996) MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J 15:5349–5357PubMedGoogle Scholar
  23. 23.
    Jung CR, Lim JH, Choi Y, Kim DG, Kang KJ, Noh SM, Im DS (2010) Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice. J Clin Invest 120:4493–4506PubMedCrossRefGoogle Scholar
  24. 24.
    Ohtsuka T, Ryu H, Minamishima YA, Ryo A, Lee SW (2003) Modulation of p53 and p73 levels by cyclin G: implication of a negative feedback regulation. Oncogene 22:1678–1687PubMedCrossRefGoogle Scholar
  25. 25.
    Bergmaschi D, Samuels V, Jin B, Duraisingham S, Crook T, Lu X (2004) ASPP1 and ASPP2: common activators of p53 family members. Mol Cell Biol 24:1341–1350CrossRefGoogle Scholar
  26. 26.
    Raman V, Martensen SA, Reisman D, Evron E, Odenwald WF, Jaffee E, Marks J, Sukumar S (2000) Compromised HOXA5 function can limit p53 expression in human breast tumours. Nature 405:974–978PubMedCrossRefGoogle Scholar
  27. 27.
    Henderson GS, van Diest PJ, Burger H, Russo J, Raman V (2006) Expression pattern of a homeotic gene, HOXA5, in normal breast and in breast tumors. Cell Oncol 28:305–313PubMedGoogle Scholar
  28. 28.
    Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res 77:81–137PubMedCrossRefGoogle Scholar
  29. 29.
    Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713PubMedGoogle Scholar
  30. 30.
    Kirsch DG, Kastan MB (1998) Tumor-suppressor p53: implications for tumor development and prognosis. J Clin Oncol 16:3158–3168PubMedGoogle Scholar
  31. 31.
    Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C (2003) Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci U S A 100:8424–8429PubMedCrossRefGoogle Scholar
  32. 32.
    Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28:622–629PubMedCrossRefGoogle Scholar
  33. 33.
    Olivier M, Langerød A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bièche I (2006) The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12:1157–1167PubMedCrossRefGoogle Scholar
  34. 34.
    Samowitz WS, Curtin K, Ma KN, Edwards S, Schaffer D, Leppert MF, Slattery ML (2002) Prognostic significance of p53 mutations in colon cancer at the population level. Int J Cancer 99:597–602PubMedCrossRefGoogle Scholar
  35. 35.
    Di Como CJ, Gaiddon C, Prives C (1999) p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 19:1438–1449PubMedGoogle Scholar
  36. 36.
    Strano S, Munarriz E, Rossi M, Cristofanelli B, Shaul Y, Castagnoli L, Levine AJ, Sacchi A, Cesareni G, Oren M (2000) Physical and functional interaction between p53 mutants and different isoforms of p73. J Biol Chem 275:29503–29512PubMedCrossRefGoogle Scholar
  37. 37.
    Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C (2001) A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 21:1874–1887PubMedCrossRefGoogle Scholar
  38. 38.
    Strano S, Fontemaggi G, Costanzo A, Rizzo MG, Monti O, Baccarini A, Del Sal G, Levrero M, Sacchi A, Oren M (2002) Physical interaction with human tumor-derived p53 mutants inhibits p63 activities. J Biol Chem 277:18817–18826PubMedCrossRefGoogle Scholar
  39. 39.
    Fang L, Lee SW, Aaronson SA (1999) Comparative analysis of p73 and p53 regulation and effector functions. J Cell Biol 147:823–830PubMedCrossRefGoogle Scholar
  40. 40.
    Shimada A, Kato S, Enjo K, Osada M, Ikawa Y, Kohno K, Obinata M, Kanamaru R, Ikawa S, Ishioka C (1999) The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. Cancer Res 59:2781–2786PubMedGoogle Scholar
  41. 41.
    Dohn M, Zhang S, Chen X (2001) p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene 20:3193–3205PubMedCrossRefGoogle Scholar
  42. 42.
    Allocati N, Di Ilio C, De Laurenzi V (2012) p63/p73 in the control of cell cycle and cell death. Exp Cell Res 318:1285–1290PubMedCrossRefGoogle Scholar
  43. 43.
    Buhlmann S, Pützer BM (2008) DNp73 a matter of cancer: mechanisms and clinical implications. Biochim Biophys Acta 1785:207–216PubMedGoogle Scholar
  44. 44.
    Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127:1323–1334PubMedCrossRefGoogle Scholar
  45. 45.
    Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665PubMedCrossRefGoogle Scholar
  46. 46.
    Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, Sanchez-Rivera FJ, Resnick R, Bronson R, Hemann MT (2010) Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468:572–575PubMedCrossRefGoogle Scholar
  47. 47.
    Junttila MR, Karnezis AN, Garcia D, Madriles F, Kortlever RM, Rostker F, Brown Swigart L, Pham DM, Seo Y, Evan GI (2010) Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468:567–571PubMedCrossRefGoogle Scholar
  48. 48.
    Wang Y, Suh YA, Fuller MY, Jackson JG, Xiong S, Terzian T, Quintás-Cardama A, Bankson JA, El-Naggar AK, Lozano G (2011) Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. J Clin Invest 121:893–904PubMedCrossRefGoogle Scholar
  49. 49.
    Essmann F, Schulze-Osthoff K (2012) Translational approaches targeting the p53 pathway for anti-cancer therapy. Br J Pharmacol 165:328–344PubMedCrossRefGoogle Scholar
  50. 50.
    Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660PubMedCrossRefGoogle Scholar
  51. 51.
    Hansemann D (1897) Die mikroscopische Diagnose der bösartigen Geschwülste. August Hirschwald, BerlinGoogle Scholar
  52. 52.
    Boveri T (1914) Zur Frage der Entstehung maligner Tumoren. Gustav Fischer Verlag, JenaGoogle Scholar
  53. 53.
    Duesberg P, Mandrioli D, McCormack A, Nicholson JM (2011) Is carcinogenesis a form of speciation? Cell Cycle 10:2100–2114PubMedCrossRefGoogle Scholar
  54. 54.
    Hanel W, Moll UM (2012) Links between mutant p53 and genomic instability. J Cell Biochem 113:433–439PubMedCrossRefGoogle Scholar
  55. 55.
    Duensing A, Duensing S (2005) Guilt by association? p53 and the development of aneuploidy in cancer. Biochem Biophys Res Commun 331:694–700PubMedCrossRefGoogle Scholar
  56. 56.
    Standfuß S, Polspisil H, Klein A (2012) SNP microarray analyses reveal copy number alterations and progressive genome reorganization during tumor development in mice breast cancer. BMC Cancer 12:380PubMedCrossRefGoogle Scholar
  57. 57.
    Klein A, Guhl E, Zollinger R, Tzeng YJ, Wessel R, Hummel M, Graessmann M, Graessmann A (2005) Gene expression profiling: cell cycle deregulation and aneuploidy do not cause breast cancer formation in WAP-SVT/t transgenic animals. J Mol Med 83:362–376PubMedCrossRefGoogle Scholar
  58. 58.
    Graessmann M, Berg B, Fuchs B, Klein A, Graessmann A (2007) Chemotherapy resistance of mouse WAP-SVT/t breast cancer cells is mediated by osteopontin, inhibiting apoptosis down-stream of caspase-3. Oncogene 26:2840–2850PubMedCrossRefGoogle Scholar
  59. 59.
    Klein A, Li N, Nicholson JM, McCormack AA, Graessmann A, Duesberg P (2010) Transgenic oncogenes induce oncogene-independent cancers with individual karyotypes and phenotypes. Cancer Genet Cytogenet 200:79–99PubMedCrossRefGoogle Scholar
  60. 60.
    Ramakers C, Ruijter JM, Deprez RH, Moorman AF (2003) Assumption-free analysis of quantitative real-time polymerase chain reaction (PCR) data. Neurosci Lett 339:62–66PubMedCrossRefGoogle Scholar
  61. 61.
    Ruijter JM, Ramakers C, Hoogaars WM, Karlen Y, Bakker O, van den Hoff MJ, Moorman AF (2009) Amplification efficiency: linking baseline and bias in the analysis of quantitative PCR data. Nucleic Acids Res 37:e45PubMedCrossRefGoogle Scholar
  62. 62.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45PubMedCrossRefGoogle Scholar
  63. 63.
    Olivier M, Hollstein M, Hainaut P (2010) TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2:a001008PubMedCrossRefGoogle Scholar
  64. 64.
    Sigal A, Rotter V (2000) Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60:6788–6793PubMedGoogle Scholar
  65. 65.
    Gualberto A, Aldape K, Kozakiewicz K, Tlsty TD (1998) An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci U S A. 95:5166–5171PubMedCrossRefGoogle Scholar
  66. 66.
    Fan S, el-Deiry WS, Bae I, Freeman J, Jondle D, Bhatia K, Fornace AJ, Magrath I, Kohn KW, O’Connor PM (1994) p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res 54:5824–5830PubMedGoogle Scholar
  67. 67.
    Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T (1994) p53 status and the efficacy of cancer therapy in vivo. Science 266:807–810PubMedCrossRefGoogle Scholar
  68. 68.
    Müer A, Overkamp T, Gillissen B, Richter A, Pretzsch T, Milojkovic A, Dörken B, Daniel PT, Hemmati P (2012) p14(ARF)-induced apoptosis in p53 protein-deficient cells is mediated by BH3-only protein-independent derepression of Bak protein through down-regulation of Mcl-1 and Bcl-xL proteins. J Biol Chem 287:17343–17352PubMedCrossRefGoogle Scholar
  69. 69.
    Weinberg RL, Veprintsev DB, Bycroft M, Fersht AR (2005) Comparative binding of p53 to its promoter and DNA recognition elements. J Mol Biol 348:589–596PubMedCrossRefGoogle Scholar
  70. 70.
    Morachis JM, Murawsky CM, Emerson BM (2010) Regulation of the p53 transcriptional response by structurally diverse core promoters. Genes Dev 24:135–147PubMedCrossRefGoogle Scholar
  71. 71.
    Tian X, Chen Y, Hu W, Wu M (2011) E2F1 inhibits MDM2 expression in a p53-dependent manner. Cell Signal 23:193–200PubMedCrossRefGoogle Scholar
  72. 72.
    Zhang X, Zhang Z, Cheng J, Li M, Wang W, Xu W, Wang H, Zhang R (2012) Transcription factor NFAT1 activates the mdm2 oncogene independent of p53. J Biol Chem 287:30468–30476PubMedCrossRefGoogle Scholar
  73. 73.
    Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24:1580–1589PubMedCrossRefGoogle Scholar
  74. 74.
    Grob TJ, Novak U, Maisse C, Barcaroli D, Lüthi AU, Pirnia F, Hügli B, Graber HU, De Laurenzi V, Fey MF (2001) Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 8:1213–1223PubMedCrossRefGoogle Scholar
  75. 75.
    Melino G, Bernassola F, Ranalli M, Yee K, Zong WX, Corazzari M, Knight RA, Green DR, Thompson C, Vousden KH (2004) p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J Biol Chem 279:8076–8083PubMedCrossRefGoogle Scholar
  76. 76.
    Pyati UJ, Gjini E, Carbonneau S, Lee JS, Guo F, Jette CA, Kelsell DP, Look AT (2011) p63 mediates an apoptotic response to pharmacological and disease-related ER stress in the developing epidermis. Dev Cell 21:492–505PubMedCrossRefGoogle Scholar
  77. 77.
    Iwakuma T, Parant JM, Fasulo M, Zwart E, Jacks T, de Vries A, Lozano G (2004) Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice. Oncogene 23:7644–7650PubMedCrossRefGoogle Scholar
  78. 78.
    Rallapalli R, Strachan G, Cho B, Mercer WE, Hall DJ (1999) A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity. J Biol Chem 274:8299–8308PubMedCrossRefGoogle Scholar
  79. 79.
    Wessel R, Foos V, Aspelmeier A, Jurgens M, Graessmann A, Klein A (2006) CorrXpression–identification of significant groups of genes and experiments by means of correspondence analysis and ratio analysis. In Silico Biol. 6:61–70PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute of BiochemistryCharité—Universitätsmedizin BerlinBerlinGermany

Personalised recommendations