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Blood, 15 July 2004, Vol. 104, No. 2, pp. 519-525. Prepublished online as a Blood First Edition Paper on March 18, 2004; DOI 10.1182/blood-2003-08-2743. This Article Full Text (PDF) All Versions of this Article: 2003-08-2743v1 104/2/519    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lunghi, P. Articles by Bonati, A. Search for Related Content PubMed PubMed Citation Articles by Lunghi, P. Articles by Bonati, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 11, 2003 Accepted March 8, 2004 Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the P73-P53AIP1 apoptotic pathway in leukemia cells Paolo Lunghi, Antonio Costanzo, Massimo Levrero, and Antonio Bonati* Department of Clinical Sciences, Section of Hemato-Oncology, University of Parma, Parma, Italy Department of Dermatology, University of Rome, Rome, Italy Laboratory of Gene Expression, Fondazione Andrea Cisalpino, University of Rome, Rome, Italy; Department of Internal Medicine, University of Cagliari, Cagliari, Italy * Corresponding author; email: antbonny{at}unipr.it. Arsenic trioxide (ATO) induces differentiation and apoptosis of malignant cells in vitro and in vivo and has been used in the treatment of a variety of hematological malignancies. We found that in NB4 acute promyelocytic and in K562 erythroleukemia cell lines treatment with the MEK1 inhibitors PD98059 and PD184352 greatly enhances apoptotic cell death induced by ATO alone. Combined treatment results in the induction of the p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1) gene in both cell lines. Since NB4 and K562 cell lines carry an inactive p53 we investigated the possible role of p73, a p53 paralog that has been shown to regulate several p53-target genes including p21, Bax and p53AIP1. We found that MEK1 inhibitors reduce the levels of dominant negative N-p73 proteins and promote the accumulation of endogenous p73a through its transcriptional activation and its tyrosine phosphorylation, resulting in p21 up-regulation and significant cell growth inhibition. ATO reduces N-p73 levels and promotes a p300-mediated acetylation of endogenous p73, thus favouring cell cycle arrest and apoptosis. Finally, the combined treatment with MEK1 inhibitors and ATO enhances the affinity of phospho-acetylated p73 for the p53AIP1 promoter in vivo, as determined by chromatin immunoprecipitation experiments, leading to p53AIP1 up-regulation and increased apoptosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. S. Dbaibo, Y. Kfoury, N. Darwiche, S. Panjarian, L. Kozhaya, R. Nasr, M. Abdallah, O. Hermine, M. El-Sabban, H. de The, et al. Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity Haematologica, June 1, 2007; 92(6): 753 - 762. [Abstract] [Full Text] [PDF] R. Lu, X. Wang, Z.-F. Chen, D.-F. Sun, X.-Q. Tian, and J.-Y. Fang Inhibition of the Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway Decreases DNA Methylation in Colon Cancer Cells J. Biol. Chem., April 20, 2007; 282(16): 12249 - 12259. [Abstract] [Full Text] [PDF] C. Bozzetti, R. Nizzoli, A. Musolino, E. M. Martella, P. Crafa, C. A. Lagrasta, R. Camisa, A. Bonati, P. Lunghi, and A. Ardizzoni p73 and p53 Pathway in Human Breast Cancers J. Clin. Oncol., April 10, 2007; 25(11): 1451 - 1453. [Full Text] [PDF] P. Lunghi, A. Costanzo, L. Salvatore, N. Noguera, L. Mazzera, A. Tabilio, F. Lo-Coco, M. Levrero, and A. Bonati MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis Blood, June 1, 2006; 107(11): 4549 - 4553. [Abstract] [Full Text] [PDF] P. Lunghi, A. Costanzo, L. Salvatore, N. Noguera, A. Tabilio, F. L. Coco, M. Levrero, and A. Bonati Arsenic Trioxide (ATO) and MEK1 Inhibitor Activate Apoptotic p73 Pathway in Primary Acute Myelogenous Leukemia Blasts. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 613 - 613. [Abstract] P. Lunghi, L. Salvatore, N. Noguera, P. Giuseppe, F. Lo, and A. Bonati MEK1 Inhibition and Arsenic Trioxide Synergize To Induce Apoptosis of Acute Myeloid Leukemia Blasts. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 3397 - 3397. [Abstract]

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