- Research Article
The cell type-specific effect of TAp73 isoforms on the cell cycle and apoptosis
Cellular & Molecular Biology Letters volume 13, pages 404–420 (2008)
p73, a member of the p53 family, exhibits activities similar to those of p53, including the ability to induce growth arrest and apoptosis. p73 influences chemotherapeutic responses in human cancer patients, in association with p53. Alternative splicing of the TP73 gene produces many p73 C- and N-terminal isoforms, which vary in their transcriptional activity towards p53-responsive promoters. In this paper, we show that the C-terminal spliced isoforms of the p73 protein differ in their DNA-binding capacity, but this is not an accurate predictor of transcriptional activity. In different p53-null cell lines, p73β induces either mitochondrial-associated or death receptor-mediated apoptosis, and these differences are reflected in different gene expression profiles. In addition, p73 induces cell cycle arrest and p21WAF1 expression in H1299 cells, but not in Saos-2. This data shows that TAp73 isoforms act differently depending on the tumour cell background, and have important implications for p73-mediated therapeutic responses in individual human cancer patients.
TRAF and TNF receptor-associated protein-22
apurinic/apyrimidinic endonuclease 1/redox factor
apoptosis stimulating proteins of p53
cyclin-dependent protein kinase-1
Dulbecco's modified Eagle medium
trail death receptor
electrophoretic mobility-shift assay
foetal bovine serum
in vitro transcription/translation
microtubule-associated protein 4
p53-induced protein with a death domain
promyelocytic leukaemia gene
SDS-polyacrylamide gel electrophoresis
TNF receptor-associated factor
Murray-Zmijewski, F., Lane, D.P. and Bourdon, J.C. p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ. 13 (2006) 962–972.
Kaghad, M., Bonnet, H., Yang, A., Creancier, L., Biscan, J.C., Valent, A., Minty, A., Chalon, P., Lelias, J.M., Dumont, X., Ferrara, P., McKeon, F. and Caput, D. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90 (1997) 809–819.
Melino, G., De Laurenzi, V. and Vousden, K.H. p73: Friend or foe in tumorigenesis. Nat. Rev. Cancer 2 (2002) 605–615.
Dominguez, G., Garcia, J.M., Pena, C., Silva, J., Garcia, V., Martinez, L., Maximiano, C., Gomez, M.E., Rivera, J.A., Garcia-Andrade, C. and Bonilla, F. DeltaTAp73 upregulation correlates with poor prognosis in human tumors: putative in vivo network involving p73 isoforms, p53, and E2F-1. J. Clin. Oncol. 24 (2006) 805–815.
Concin, N., Becker, K., Slade, N., Erster, S., Mueller-Holzner, E., Ulmer, H., Daxenbichler, G., Zeimet, A., Zeillinger, R., Marth, C. and Moll, U.M. Transdominant DeltaTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Res. 64 (2004) 2449–2460.
Deyoung, M.P. and Ellisen, L.W. p63 and p73 in human cancer: defining the network. Oncogene 26 (2007) 5169–5183.
Coates, P.J. Regulating p73 isoforms in human tumours. J. Pathol. 210 (2006) 385–389.
Flores, E.R., Tsai, K.Y., Crowley, D., Sengupta, S., Yang, A., McKeon, F. and Jacks, T. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416 (2002) 560–564.
Irwin, M.S., Kondo, K., Marin, M.C., Cheng, L.S., Hahn, W.C. and Kaelin, W.G., Jr. Chemosensitivity linked to p73 function. Cancer Cell 3 (2003) 403–410.
Rocco, J.W., Leong, C.O., Kuperwasser, N., DeYoung, M.P. and Ellisen, L.W. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9 (2006) 45–56.
Vojtesek, B., Bartek, J., Midgley, C.A. and Lane, D.P. An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. J. Immunol. Methods 151 (1992) 237–244.
Chen, J., Marechal, V. and Levine, A.J. Mapping of the p53 and mdm-2 interaction domains. Mol. Cell. Biol. 13 (1993) 4107–4114.
Fredersdorf, S., Milne, A.W., Hall, P.A. and Lu, X. Characterization of a panel of novel anti-p21Waf1/Cip1 monoclonal antibodies and immunochemical analysis of p21Waf1/Cip1 expression in normal human tissues. Am. J. Pathol. 148 (1996) 825–835.
Masuda, H., Miller, C., Koeffler, H.P., Battifora, H. and Cline, M.J. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc. Natl. Acad. Sci. U S A 84 (1987) 7716–7719.
Bodner, S.M., Minna, J.D., Jensen, S.M., D'Amico, D., Carbone, D., Mitsudomi, T., Fedorko, J., Buchhagen, D.L., Nau, M.M. and Gazdar, A.F. Expression of mutant p53 proteins in lung cancer correlates with the class of p53 gene mutation. Oncogene 7 (1992) 743–749.
Sambrook, J., Fritsch, E.F. and Maniatis, T. Assay for β-Galactosidase in Extracts of Mammalian Cells. in: Molecular cloning, 2th edition, Cold Spring Harbor Laboratory Press, 1989, 16.66–16.67.
Thurfjell, N., Coates, P.J., Uusitalo, T., Mahani, D., Dabelsteen, E., Dahlqvist, A., Sjostrom, B., Roos, G. and Nylander, K. Complex p63 mRNA isoform expression patterns in squamous cell carcinoma of the head and neck. Int. J. Oncol. 25 (2004) 27–35.
Boldrup, L., Bourdon, J.C., Coates, P.J., Sjostrom, B. and Nylander, K. Expression of p53 isoforms in squamous cell carcinoma of the head and neck. Eur. J. Cancer 43 (2007) 617–623.
Lohr, K., Moritz, C., Contente, A. and Dobbelstein, M. p21/CDKN1A mediates negative regulation of transcription by p53. J. Biol. Chem. 278 (2003) 32507–32516.
Grob, T.J., Novak, U., Maisse, C., Barcaroli, D., Luthi, A.U., Pirnia, F., Hugli, B., Graber, H.U., De Laurenzi, V., Fey, M.F., Melino, G. and Tobler, A. Human delta Np73 regulates a dominant negative feedback loop for TAp73 and p53. Cell. Death. Differ. 8 (2001) 1213–1223.
Ueda, Y., Hijikata, M., Takagi, S., Chiba, T. and Shimotohno, K. Transcriptional activities of p73 splicing variants are regulated by intervariant association. Biochem. J. 356 (2001) 859–866.
Brazda, V., Muller, P., Brozkova, K. and Vojtesek, B. Restoring wild-type conformation and DNA-binding activity of mutant p53 is insufficient for restoration of transcriptional activity. Biochem. Biophys. Res. Commun 351 (2006) 499–506.
Bernassola, F., Salomoni, P., Oberst, A., Di Como, C.J., Pagano, M., Melino, G. and Pandolfi, P.P. Ubiquitin-dependent degradation of p73 is inhibited by PML. J. Exp. Med. 199 (2004) 1545–1557.
Murphy, M., Ahn, J., Walker, K.K., Hoffman, W.H., Evans, R.M., Levine, A.J. and George, D.L. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes. Dev. 13 (1999) 2490–2501.
Lanza, M., Marinari, B., Papoutsaki, M., Giustizieri, M.L., D'Alessandra, Y., Chimenti, S., Guerrini, L. and Costanzo, A. Cross-talks in the p53 family: deltaNp63 is an anti-apoptotic target for deltaNp73alpha and p53 gain-offunction mutants. Cell Cycle 5 (2006) 1996–2004.
Terrasson, J., Allart, S., Martin, H., Lule, J., Haddada, H., Caput, D. and Davrinche, C. p73-dependent apoptosis through death receptor: impairment by human cytomegalovirus infection. Cancer Res. 65 (2005) 2787–2794.
Glasgow, J.N., Qiu, J., Rassin, D., Grafe, M., Wood, T. and Perez-Pol, J.R. Transcriptional regulation of the BCL-X gene by NF-kappaB is an element of hypoxic responses in the rat brain. Neurochem. Res. 26 (2001) 647–659.
Reed, J.C. Apoptosis-targeted therapies for cancer. Cancer Cell 3 (2003) 17–22.
These authors contributed equally to this paper
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Holcakova, J., Ceskova, P., Hrstka, R. et al. The cell type-specific effect of TAp73 isoforms on the cell cycle and apoptosis. Cell Mol Biol Lett 13, 404–420 (2008). https://doi.org/10.2478/s11658-008-0011-z