p73 and caspase-cleaved p73 fragments localize to mitochondria and augment TRAIL-induced apoptosis

AE Sayan, BS Sayan, V Gogvadze, D Dinsdale, U Nyman, TM Hansen, B Zhivotovsky, GM Cohen, RA Knight and G Melino


Oncogene (2008) 27, 4363–4372


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The p73 protein, a member of the p53 family, has both developmental and tumorigenic functions. Here we show that p73 is cleaved by caspase-3 and -8 both in vitro and in vivo during apoptosis elicited by DNA-damaging drugs and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor ligation. TAp73 and some of its cleavage products are localized to mitochondria. siRNA-mediated downregulation of p73 expression induced a small but significant change in the susceptibility of HCT116 cells to TRAIL-induced apoptosis. A transcription- deficient mutant of TAp73 enhanced TRAIL-induced apoptosis suggesting that p73 protein has transcriptionindependent functions during death receptor-mediated apoptosis. Additionally, recombinant p73 protein induced cytochrome c release from isolated mitochondria providing evidence that nonnuclear p73 may have additional functions in the progression of apoptosis.


Agami R, Blandino G, Oren M, Shaul Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399: 809–813.

Aqeilan RI, Pekarsky Y, Herrero JJ, Palamarchuk A, Letofsky J, Druck T et al. (2004). Functional association between Wwox tumor suppressor protein and p73, a p53 homolog. Proc Natl Acad Sci USA 101: 4401–4406.

Asher G, Tsvetkov P, Kahana C, Shaul Y. (2005). A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev 19: 316–321.

Bernassola F, Salomoni P, OberstA, Di Como CJ, Pagano M, Melino G et al. (2004). Ubiquitin-dependent degradation of p73 is inhibited by PML. J Exp Med 199: 1545–1557.

Chipuk JE, Bouchier-Hayes L, Kuwana T, Newmeyer DD, Green DR. (2005). PUMA couples the nuclear and cytoplasmic proapoptotic function of p53. Science 309: 1732–1735.

Chipuk JE, Green DR. (2006). Dissecting p53-dependent apoptosis. Cell Death Differ 13: 994–1002.

Chipuk JE, Maurer U, Green DR, Schuler M. (2003). Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4: 371–381.

Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA et al. (2002). DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Mol Cell 9: 175–186.

De Laurenzi V, Costanzo A, Barcaroli D, Terrinoni A, Falco M, Annicchiarico-Petruzzelli M et al. (1998). Two new p73 splice variants, gamma and delta, with different transcriptional activity. J Exp Med 188: 1763–1768.

Essmann F, Pohlmann S, Gillissen B, Daniel PT, Schulze-Osthoff K, Janicke RU. (2005). Irradiation-induced translocation of p53 to mitochondria in the absence of apoptosis. J Biol Chem 280: 37169–37177.

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

Grob TJ, Novak U, Maisse C, Barcaroli D, Luthi AU, Pirnia F et al. (2001). Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell Death Differ 8: 1213–1223.

Lamkanfi M, Festjens N, Declercq W, Vanden Berghe T, Vandenabeele P. (2007). Caspases in cell survival, proliferation and differentiation. Cell Death Differ 14: 44–55.

Leu JI, DumontP, Hafey M, Murphy ME, George DL. (2004). Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6: 443–450.

Luo X, Budihardjo I, Zou H, Slaughter C, Wang X. (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.

Luthi AU, Martin SJ. (2007). The CASBAH: a searchable database of caspase substrates. Cell Death Differ 14: 641–650.

MacLachlan TK, El-Deiry WS. (2002). Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc Natl Acad Sci USA 99: 9492–9497.

Mahyar-Roemer M, Fritzsche C, Wagner S, Laue M, Roemer K. (2004). Mitochondrial p53 levels parallel total p53 levels independent of stress response in human colorectal carcinoma and glioblastoma cells. Oncogene 23: 6226–6236.

Mantovani F, Piazza S, Gostissa M, Strano S, Zacchi P, Mantovani R et al. (2004). Pin1 links the activities of c-Abl and p300 in regulating p73 function. Mol Cell 14: 625–636.

Marchenko ND, Zaika A, Moll UM. (2000). Death signal-induced localization of p53 protein to mitochondria. A potential role in apoptotic signaling. J Biol Chem 275: 16202–16212.

Melino G, Bernassola F, Ranalli M, Yee K, Zong WX, Corazzari M et al. (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, KnightRA. (2003). Functional regulation of p73 and p63: development and cancer. Trends Biochem Sci 28: 663–670.

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590.

Muller M, Schilling T, Sayan AE, KairatA, Lorenz K, Schulze- Bergkamen H et al. (2005). TAp73/deltaNp73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma. Cell Death Differ 12: 1564–1577.

Munarriz E, Bano D, Sayan AE, Rossi M, Melino G, Nicotera P. (2005). Calpain cleavage regulates the protein stability of p73. Biochem Biophys Res Commun 333: 954–960.

OberstA, Rossi M, Salomoni P, Pandolfi PP, Oren M, Melino G et al. (2005). Regulation of the p73 protein stability and degradation. Biochem Biophys Res Commun 331: 707–712.

Ozoren N, El-Deiry WS. (2002). Defining characteristics of types I and II apoptotic cells in response to TRAIL. Neoplasia 4: 551–557.

Rossi M, De Laurenzi V, Munarriz E, Green DR, Liu YC, Vousden KH et al. (2005). The ubiquitin-protein ligase Itch regulates p73 stability. EMBO J 24: 836–848.

Sayan AE, Paradisi A, Vojtesek B, Knight RA, Melino G, Candi E. (2005). New antibodies recognizing p73: comparison with commercial antibodies. Biochem Biophys Res Commun 330: 186–193.

Sayan AE, Sayan BS, Findikli N, Ozturk M. (2001). Acquired expression of transcriptionally active p73 in hepatocellular carcinoma cells. Oncogene 20: 5111–5117.

Sayan BS, Sayan AE, KnightRA, Melino G, Cohen GM. (2006). p53 is cleaved by caspases generating fragments localizing to mitochondria. J Biol Chem 281: 13566–13573.

Sayan BS, Sayan AE, Yang AL, Aqeilan RI, Candi E, Cohen GM et al. (2007). Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis. Proc Natl Acad Sci USA 104: 10871–10876.

Schembri L, DalibartR, Tomasello F, Legembre P, Ichas F, De Giorgi F. (2007). The HA tag is cleaved and loses immunoreactivity during apoptosis. Nat Methods 4: 107–108.

Sigal A, Rotter V. (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 60: 6788–6793.

Stiewe T, Putzer BM. (2000). Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet 26: 464–469.

Stiewe T, Zimmermann S, Frilling A, Esche H, Putzer BM. (2002). Transactivation-deficient deltaTA-p73 acts as an oncogene. Cancer Res 62: 3598–3602.

Sun XM, MacFarlane M, Zhuang J, Wolf BB, Green DR, Cohen GM. (1999). Distinct caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. J Biol Chem 274: 5053–5060.

Takimoto R, El-Deiry WS. (2000). Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 19: 1735–1743.

Toledo F, Wahl GM. (2006). Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat Rev Cancer 6: 909–923.

Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C et al. (2006). WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J Biol Chem 281: 8600–8606.

Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J et al. (2000). p73-deficientmice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404: 99–103.

Zaika AI, Kovalev S, Marchenko ND, Moll UM. (1999). Overexpression of the wild type p73 gene in breast cancer tissues and cell lines. Cancer Res 59: 3257–3263.

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