ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells

Venturina Stagni, Maria Giovanna Di Bari, Silvia Cursi, Ivano Condò, Maria Teresa Cencioni, Roberto Testi, Yaniv Lerenthal, Enrico Cundari, Daniela Barilà

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Ataxia telangiectasia (A-T) is a rare cancer-predisposing genetic disease, caused by the lack of functional ATM kinase, a major actor of the double strand brakes (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 pharmacologic ATM kinase inactivation resulted in FLIP protein up-regulation 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.

Original languageEnglish
Pages (from-to)829-837
Number of pages9
JournalBlood
Volume111
Issue number2
DOIs
Publication statusPublished - Jan 15 2008

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Automatic teller machines
Ataxia Telangiectasia
Phosphotransferases
Lymphocytes
Apoptosis
Lymphoma
Hodgkin Disease
Immune system
Immune System
Homeostasis
Up-Regulation
Inborn Genetic Diseases
Proteins
Autoimmunity
DNA Damage
Leukemia
Brakes
Phenotype
Cells
Defects

ASJC Scopus subject areas

  • Hematology

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ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells. / Stagni, Venturina; Di Bari, Maria Giovanna; Cursi, Silvia; Condò, Ivano; Cencioni, Maria Teresa; Testi, Roberto; Lerenthal, Yaniv; Cundari, Enrico; Barilà, Daniela.

In: Blood, Vol. 111, No. 2, 15.01.2008, p. 829-837.

Research output: Contribution to journalArticle

Stagni, V, Di Bari, MG, Cursi, S, Condò, I, Cencioni, MT, Testi, R, Lerenthal, Y, Cundari, E & Barilà, D 2008, 'ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells', Blood, vol. 111, no. 2, pp. 829-837. https://doi.org/10.1182/blood-2007-04-085399
Stagni, Venturina ; Di Bari, Maria Giovanna ; Cursi, Silvia ; Condò, Ivano ; Cencioni, Maria Teresa ; Testi, Roberto ; Lerenthal, Yaniv ; Cundari, Enrico ; Barilà, Daniela. / ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells. In: Blood. 2008 ; Vol. 111, No. 2. pp. 829-837.
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