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 language | English |
|---|---|
| Pages (from-to) | 829-837 |
| Number of pages | 9 |
| Journal | Blood |
| Volume | 111 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Jan 15 2008 |
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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 journal › Article
}
TY - JOUR
T1 - ATM kinase activity modulates Fas sensitivity through the regulation of FLIP in lymphoid cells
AU - Stagni, Venturina
AU - Di Bari, Maria Giovanna
AU - Cursi, Silvia
AU - Condò, Ivano
AU - Cencioni, Maria Teresa
AU - Testi, Roberto
AU - Lerenthal, Yaniv
AU - Cundari, Enrico
AU - Barilà, Daniela
PY - 2008/1/15
Y1 - 2008/1/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38349087547&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38349087547&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-04-085399
DO - 10.1182/blood-2007-04-085399
M3 - Article
C2 - 17932249
AN - SCOPUS:38349087547
VL - 111
SP - 829
EP - 837
JO - Blood
JF - Blood
SN - 0006-4971
IS - 2
ER -