Abstract
The tumor suppressor p53 protein is activated by genotoxic stress and regulates genes involved in senescence, apoptosis and cell-cycle arrest. Nine p53 isoforms have been described that may modulate suppressive functions of the canonical p53 protein. Among them, Δ133p53 lacks the 132 proximal residues and has been shown to modulate p53-induced apoptosis and cell-cycle arrest. Δ133p53 is expressed from a specific mRNA, p53I4, driven by an alternative promoter P2 located between intron 1 and exon 5 of TP53 gene. Here, we report that the P2 promoter is regulated in a p53-dependent manner. Δ133p53 expression is increased in response to DNA damage by doxorubicin in p53 wild-type cell lines, but not in p53-mutated cells. Chromatin immunoprecipitation and luciferase assays using P2 promoter deletion constructs indicate that p53 binds functional response elements located within the P2 promoter. We also show that Δ133p53 does not bind specifically to p53 consensus DNA sequence in vitro, but competes with wild-type p53 in specific DNA-binding assays. Finally, we report that Δ133p53 counteracts p53-dependent growth suppression in clonogenic assays. These observations indicate that Δ133p53 is a novel target of p53 that may participate in a negative feedback loop controlling p53 function.
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References
Bacus SS, Yarden Y, Oren M, Chin DM, Lyass L, Zelnick CR et al. (1996). Neu differentiation factor (Heregulin) activates a p53-dependent pathway in cancer cells. Oncogene 12: 2535–2547.
Boldrup L, Bourdon JC, Coates PJ, Sjostrom B, Nylander K . (2007). Expression of p53 isoforms in squamous cell carcinoma of the head and neck. Eur J Cancer 43: 617–623.
Bourdon JC . (2007). p53 and its isoforms in cancer. Br J Cancer 97: 277–282.
Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP et al. (2005). p53 isoforms can regulate p53 transcriptional activity. Genes Dev 19: 2122–2137.
Cartharius K, Frech K, Grote K, Klocke B . (2005). MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21: 2933–2942.
Chen J, Ng SM, Chang C, Zhang Z, Bourdon JC, Lane DP et al. (2009). p53 isoform delta113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes Dev 23: 278–290.
Chen J, Ruan H, Ng SM, Gao C, Soo HM, Wu W et al. (2005). Loss of function of def selectively up-regulates Delta113p53 expression to arrest expansion growth of digestive organs in zebrafish. Genes Dev 19: 2900–2911.
Cho Y, Gorina S, Jeffrey PD, Pavletich NP . (1994). Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265: 346–355.
Courtois S, Verhaegh G, North S, Luciani MG, Lassus P, Hibner U et al. (2002). DeltaN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53. Oncogene 21: 6722–6728.
Danilova N, Sakamoto KM, Lin S . (2008). Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood 112: 5228–5237.
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.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM et al. (1993). WAF1, a potential mediator of p53 tumor suppression. Cell 75: 817–825.
Ghosh A, Stewart D, Matlashewski G . (2004). Regulation of human p53 activity and cell localization by alternative splicing. Mol Cell Biol 24: 7987–7997.
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.
Harmes DC, Bresnick E, Lubin EA, Watson JK, Heim KE, Curtin JC et al. (2003). Positive and negative regulation of deltaN-p63 promoter activity by p53 and deltaN-p63-alpha contributes to differential regulation of p53 target genes. Oncogene 22: 7607–7616.
Haupt Y, Maya R, Kazaz A, Oren M . (1997). Mdm2 promotes the rapid degradation of p53. Nature 387: 296–299.
Hurd C, Khattree N, Dinda S, Alban P, Moudgil VK . (1997). Regulation of tumor suppressor proteins, p53 and retinoblastoma, by estrogen and antiestrogens in breast cancer cells. Oncogene 15: 991–995.
Ishimoto O, Kawahara C, Enjo K, Obinata M, Nukiwa T, Ikawa S . (2002). Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73. Cancer Res 62: 636–641.
Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A et al. (1997). Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90: 809–819.
Kubbutat MH, Jones SN, Vousden KH . (1997). Regulation of p53 stability by Mdm2. Nature 387: 299–303.
Marcel V, Hainaut P . (2009). p53 isoforms—a conspiracy to kidnap p53 tumor suppressor activity? Cell Mol Life Sci 66: 391–406.
Menendez D, Inga A, Jordan JJ, Resnick MA . (2007). Changing the p53 master regulatory network: ELEMENTary, my dear Mr Watson. Oncogene 26: 2191–2201.
Miyashita T, Reed JC . (1995). Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80: 293–299.
Murray-Zmijewski F, Lane DP, Bourdon JC . (2006). p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress. Cell Death Differ 13: 962–972.
Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M . (2007). TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26: 2157–2165.
Tuck SP, Crawford L . (1989). Characterization of the human p53 gene promoter. Mol Cell Biol 9: 2163–2172.
Verhaegh GW, Richard MJ, Hainaut P . (1997). Regulation of p53 by metal ions and by antioxidants: dithiocarbamate down-regulates p53 DNA-binding activity by increasing the intracellular level of copper. Mol Cell Biol 17: 5699–5706.
Villunger A, Michalak EM, Coultas L, Müllauer F, Böck G, Ausserlechner MJ et al. (2003). p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 302: 1036–1038.
Vousden K . (2006). Outcomes of p53 activation—spoilt for choice. J Cell Sci 119: 5015–5020.
Waldman T, Kinzler KW, Vogelstein B . (1995). p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res 55: 5187–5190.
Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V et al. (1998). p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2: 305–316.
Acknowledgements
VM is supported by la Ligue National Contre le Cancer. LF-C is supported by The Association for International Cancer Research (AICR). This project is funded by la Ligue Régionale du Rhône Contre le Cancer.
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Marcel, V., Vijayakumar, V., Fernández-Cuesta, L. et al. p53 regulates the transcription of its Δ133p53 isoform through specific response elements contained within the TP53 P2 internal promoter. Oncogene 29, 2691–2700 (2010). https://doi.org/10.1038/onc.2010.26
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DOI: https://doi.org/10.1038/onc.2010.26
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