Importance of PIKKs in NF-¦ÊB activation by genotoxic stress

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• 作者：Hé ; lè ; ne Sabatel ; Cé ; line Pirlot ; Jacques Piette ; Yvette Habraken  ; ;   ; ^{yvette.habraken@ulg.ac.be}
• 关键词：DNA double-strand breaks ; Replication stress ; ATM ; ATR ; NF-¦ÊB
• 刊名：Biochemical Pharmacology
• 出版年：2011
• 出版时间：15 November 2011
• 年：2011
• 卷：82
• 期：10
• 页码：1371-1383
• 全文大小：1079 K

文摘

Alteration of the genome integrity leads to the activation of a vast network of cellular responses named ¡°DNA damage response? Three kinases from the phosphoinositide 3-kinase-like protein kinase family regulate this network; ATM and DNA-PK both activated by DNA double-strand breaks and ATR activated by replication blocks. ¡°DNA damage response?pathway coordinates cell cycle arrest, DNA repair, and the activation of transcription factors such as p53 and NF-¦ÊB. It controls senescence/apoptosis/survival of the damaged cells. Cell death or survival result from a tightly regulated balance between antagonist pro- and anti-apoptotic signals. NF-¦ÊB is a key transcription factor involved in immunity, inflammation and cell transformation. When activated by DNA double-strand breaks, NF-¦ÊB has most often a pro-survival effect and thereof interferes with chemotherapy treatments that often rely on DNA damage to induce tumor cell death (i.e. topoisomerase inhibitors and ionizing radiation). NF-¦ÊB is thus an important pharmaceutical target. Agents leading to replication stress induce a pro-apoptotic NF-¦ÊB. The molecular mechanisms initiated by DNA lesions leading to NF-¦ÊB nuclear translocation have been extensively studied these last years. In this review, we will focus on ATM, ATR and DNA-PK functions both in the IKK¦Á/IKK¦Â/NEMO-dependent or -independent signaling pathways and on the regulation they can exercise at the promoter level of NF-¦ÊB regulated genes.