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Blood, 15 January 2008, Vol. 111, No. 2, pp. 829-837. Prepublished online as a Blood First Edition Paper on October 11, 2007; DOI 10.1182/blood-2007-04-085399. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-085399v1 111/2/829    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stagni, V. Articles by Barila, D. Search for Related Content PubMed PubMed Citation Articles by Stagni, V. Articles by Barila, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 16, 2007 Accepted October 2, 2007 ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells Venturina Stagni, Maria Giovanna di Bari, Silvia Cursi, Ivano Condo, Maria Teresa Cencioni, Roberto Testi, Yaniv Lerenthal, Enrico Cundari, and Daniela Barila* Dulbecco Telethon Institute, Dept of Experimental Medicine & Biochemical Sciences, University of Rome "Tor Vergata", Rome, Italy Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy Laboratory of Immunology & Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome, Italy Laboratory of Neuroimmunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Istituto di Biologia e Patologia Molecolari Consiglio Nazionale delle Ricerche, Rome, Italy * Corresponding author; email: daniela.barila{at}uniroma2.it. Ataxia Telangiectasia (A-T) is a rare cancer-predisposing genetic disease, caused by the lack of functional ATM kinase, a major actor of the DSB DNA-damage response. A-T patients show a broad and diverse phenotype, which includes an increased rate of lymphoma and leukemia development. Fas-induced apoptosis plays a fundamental role in the homeostasis of the immune system and its defects have been associated with autoimmunity and lymphoma development. We therefore investigated the role of ATM kinase in Fas-induced apoptosis. Using A-T lymphoid cells we could show that ATM deficiency causes resistance to Fas-induced apoptosis. A-T cells upregulate FLIP protein levels, a well-known inhibitor of Fas-induced apoptosis. Reconstitution of ATM kinase activity was sufficient to decrease FLIP levels and to restore Fas-sensitivity. Conversely, genetic and pharmacological ATM kinase inactivation resulted in FLIP protein upregulation and Fas resistance. Both ATM and FLIP are aberrantly regulated in Hodgkin lymphoma. Importantly, we found that reconstitution of ATM kinase activity decreases FLIP protein levels and restores Fas-sensitivity in Hodgkin lymphoma derived cells. Overall, these data identify a novel molecular mechanism through which ATM kinase may regulate the immune system homeostasis and impair lymphoma development. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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