TAp63a induces apoptosis by activating signaling via death receptors and mitochondria

Olav Gressner, Tobias Schilling, Katja Lorenz, Elisa Schulze Schleithoff, Andreas Koch, Henning Schulze-Bergkamen, Anna Maria Lena, Eleonora Candi, Alessandro Terrinoni, Maria Valeria Catani, Moshe Oren, Gerry Melino, Peter H Krammer, Wolfgang Stremmel and Martina Muller


The EMBO Journal (2005) 24, 2458–2471


Читать статью


TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DNp63. We investigated the downstream mechanisms by which TAp63a elicits apoptosis. TAp63a directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63a can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63a and the mitochondrial apoptosis pathway. TAp63a upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63a is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63a in the induction of apoptosis and chemosensitivity.


Agami R, Blandino G, Oren M, Shaul Y (1999) Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399: 809

Ben Yehoyada M, Ben Dor I, Shaul Y (2003) c-Abl tyrosine kinase selectively regulates p73 nuclear matrix association. J Biol Chem 278: 34475–34482

Benchimol S (2004) p53—an examination of sibling support in apoptosis control. Cancer Cell 6: 3–4

Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M (2001) Minimum information about a microarray experiment (MIAME)—toward standards for microarray data. Nat Genet 29: 365–371

Casciano I, Mazzocco K, Boni L, Pagnan G, Banelli B, Allemanni G, Ponzoni M, Tonini GP, Romani M (2002) Expression of DeltaNp73 is a molecular marker for adverse outcome in neuroblastoma patients. Cell Death Differ 9: 246–251

Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, Newbury-Ecob R, Hennekam RC, Van Buggenhout G, van Haeringen A, Woods CG, van Essen AJ, de Waal R, Vriend G, Haber DA, Yang A, McKeon F, Brunner HG, van Bokhoven H (1999) Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99: 143–153

Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA, Fontemaggi G, Fanciulli M, Schiltz L, Blandino G, Balsano C, Levrero M (2002) DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol Cell 9: 175–186

Dhein J, Daniel PT, Trauth BC, Oehm A, Mo¨ ller P, Krammer PH (1992) Induction of apoptosis by monoconal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J Immunol 149: 3166–3173

El-Deiry WS, Kern SE, Pietenpol JA, Kinzler KW, Vogelstein B (1992) Definition of a consensus binding site for p53. Nat Genet 1: 45–49

Flores ER, Tsai KY, Crowley D, Sengupta S, Yang A, McKeon F, Jacks T (2002) p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416: 560–564

Ganten TM, Haas TL, Sykora J, Stahl H, Sprick MR, Fas SC, Krueger A, Weigand MA, Grosse-Wilde A, Stremmel W, Krammer PH, Walczak H (2004) Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugs. Cell Death Differ 11 (Suppl 1): S86–S96

Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin JrWG, Levrero M, Wang JY (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399: 806–809

Gonzalez S, Prives C, Cordon-Cardo C (2003) p73alpha regulation by Chk1 in response to DNA damage. Mol Cell Biol 23: 8161–8171

Gupta S, Radha V, Furukawa Y, Swarup G (2001) Direct transcriptional activation of human caspase-1 by tumor suppressor p53. J Biol Chem 276: 10585–10588

He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95: 2509–2514

Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC, Kaelin WG (2003) Chemosensitivity linked to p73 function. Cancer Cell 3: 403–410

Kissil JL, Cohen O, Raveh T, Kimchi A (1999) Structure–function analysis of an evolutionary conserved protein, DAP3, which mediates TNF-alpha- and Fas-induced cell death. EMBO J 18: 353–362

Lee SY, Choi Y (1997) TRAF-interacting protein (TRIP): a novel component of the tumor necrosis factor receptor (TNFR)- and CD30-TRAF signaling complexes that inhibits TRAF2-mediated NF-kappaB activation. J Exp Med 185: 1275–1285

Liedtke C, Groger N, Manns MP, Trautwein C (2003) The human caspase-8 promoter sustains basal activity through SP1 and ETS-like transcription factors and can be up-regulated by a p53-dependent mechanism. J Biol Chem 278: 27593–27604

Liu X, Yue P, Khuri FR, Sun SY (2004) p53 upregulates death receptor 4 expression through an intronic p53 binding site. Cancer Res 64: 5078–5083

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: 8076–8083

Melino G, De Laurenzi V, Vousden KH (2002) p73: friend or foe in tumorigenesis. Nat Rev Cancer 2: 605–615

Melino G, Lu X, Gasco M, Crook T, Knight RA (2003) Functional regulation of p73 and p63: development and cancer. Trends Biochem Sci 28: 663–670

Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398: 708–713

Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293–299

Miyazaki T, Reed JC (2001) A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins. Nat Immunol 2: 493–500

Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2: 371–386

Mukamel Z, Kimchi A (2004) Death-associated protein 3 localizes to the mitochondria and is involved in the process of mitochondrial fragmentation during cell death. J Biol Chem 279: 36732–36738

Mu¨ ller M, Strand S, Hug H, Heinemann EM, Walczak H, Hofmann WJ, Stremmel W, Krammer PH, Galle PR (1997) Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest 99: 403–413

Mu¨ ller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, StremmelW, Oren M, Krammer PH (1998) p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188: 2033–2045

Nicoletti I, Migliorati G, Paggliacci MC, Grignani F, Riccardi C (1991) A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods 139: 271–279

Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S (1998)Cloning and functional analysis of human p51, which structurally and functionally resembles p53 [see comments] [published erratum appears in Nat Med 1998 Sep;4(9):982]. Nat Med 4: 839–843

Pellegrini G, Dellambra E, Golisano O, Martinelli E, Fantozzi I, Bondanza S, Ponzin D, McKeon F, De Luca M (2001) p63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA 98: 3156–3161

Petitjean A, Cavard C, Shi H, Tribollet V, Hainaut P, Caron dF (2005) The expression of TA and DeltaNp63 are regulated by different mechanisms in liver cells. Oncogene 24: 512–519

Senoo M, Manis JP, Alt FW, McKeon F (2004) p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. Cancer Cell 6: 85–89

The Tumor Analysis Best Practices Working Group (2004) Expression profiling—best practices for data generation and interpretation in clinical trials. Nat Rev Genet 5: 229–237

Trauth BC, Klas C, Peters AJM, Matzku S, Mo¨ ller P, Falk W, Debatin KM, Krammer PH (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301–305

Vousden KH (2000) p53: death star. Cell 103: 691–694 Wada N, Matsumura M, Ohba Y, Kobayashi N, Takizawa T, Nakanishi Y (1995) Transcription stimulation of the Fas-encoding gene by nuclear factor for interleukin-6 expression upon influenza virus infection. J Biol Chem 270: 18007–18012

Westfall MD, Pietenpol JA (2004) p63: molecular complexity in development and cancer. Carcinogenesis 25: 857–864

White E, Prives C (1999) DNA damage enables p73. Nature 399: 734–737

Wu G, Osada M, Guo Z, Fomenkov A, Begum S, Zhao M, Upadhyay S, Xing M, Wu F, Moon C, Westra WH, Koch WM, Mantovani R, Califano JA, Ratovitski E, Sidransky D, Trink B (2005) DeltaNp63alpha up-regulates the Hsp70 gene in human cancer.
Cancer Res 65: 758–766

Wu GS, Burns TF, McDonald ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, El-Deiry WS (1997) KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene [letter]. Nat Genet 17: 141–143

Yang A, Kaghad M, Caput D, McKeon F (2002) On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 18: 90–95

Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398: 714–718

Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S,Weichselbaum R, Kufe D (1999) p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399: 814–817

Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, Chalas E, Moll UM (2002) DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med 196: 765–780

Zuliani T, Duval R, Jayat C, Schnebert S, Andre P, Dumas M, RatinaudMH (2003) Sensitive and reliable JC-1 and TOTO-3 double staining to assess mitochondrial transmembrane potential and plasma membrane integrity: interest for cell death investigations.
Cytometry 54A: 100–108

Прочитано 3067 раз
Оцените материал
(0 голосов)
Опубликовано в СТАТЬИ
Авторизуйтесь, чтобы получить возможность оставлять комментарии


Управление научных исследований СПбГТИ (ТУ)

Горячие новости

Приборное оснащение лаборатории

Rambler's Top100
//'+ 'Рейтинг@Mail.ru<\/a><\/p>');})(window,navigator,document);//]]>