PIDD Mediates NF-κB Activation in Response to DNA Damage

Janssens, Sophie; Tinel, Antoine; Lippens, Saskia; Tschopp, Jürg

doi:10.1016/j.cell.2005.09.036

Cited by 302 publications

(334 citation statements)

References 45 publications

(61 reference statements)

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“…In the course of a response to DNA damage, NEMO is sequentially sumoylated, phosphorylated and ubiquitinated to activate NF-kB (Huang et al, 2003;Hay, 2004). PIDD isoform 1 is essential for NEMO sumoylation and its overexpression increases SUMO-NEMO levels (Janssens et al, 2005). Figure 4d shows that all the PIDD isoforms when overexpressed in HEK293T cells enhanced NEMO sumoylation in response to etoposide treatment.…”

Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbmentioning

confidence: 98%

“…The 11 amino-acid deletion in isoform 2 encompasses the second cleavage site used for PIDD The two C terminal fragments generated by PIDD autoprocessing have distinct functions (Tinel et al, 2007). PIDD-C is able to interact with RIP1 and NEMO to activate NF-kB in response to DNA damage (Janssens et al, 2005). In contrast, PIDD-CC interacts with RAIDD and caspase-2 to form the so-called PIDDosome (Tinel and Tschopp, 2004), a molecular platform that induces caspase-2 activation and cleavage.…”

Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbmentioning

confidence: 99%

“…Further characterization of PIDD indicated that it could act as a switch between cell survival and cell death in response to DNA damage. Our group has shown that PIDD is able to interact with receptor interacting protein 1 (RIP1) and NF-kB essential modifier (NEMO) leading to NEMO sumoylation and NF-kB activation in response to DNA damage (Janssens et al, 2005). We also demonstrated that PIDD is able to form a caspase-2-activating platform by recruiting the adapter molecule RIP-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD) and thus sensitize cells to genotoxic stress (Tinel and Tschopp, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The latter, which can be induced by topoisomerase inhibitors as well as IR, are extremely toxic and can lead to chromosomal aberrations and genetic instability (van Gent et al, 2001). Activation of NF-kB in response to DSB depends on two parallel signaling cascades, namely those orchestrated by the PI3 kinase like ataxia-telangectasia mutated (ATM), which is activated by DSB or higher order chromatin changes (Bakkenist and Kastan, 2003) and those regulated by PIDD, which is activated by an as yet unknown signal (Janssens et al, 2005). In response to DSB, NEMO (also known as IKKg) is sumoylated on K277 and K309 by PIASg in a PIDD-dependent fashion, and SUMO-NEMO accumulates in the nucleus (Huang et al, 2003;Janssens et al, 2005;Mabb et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of NF-kB in response to DSB depends on two parallel signaling cascades, namely those orchestrated by the PI3 kinase like ataxia-telangectasia mutated (ATM), which is activated by DSB or higher order chromatin changes (Bakkenist and Kastan, 2003) and those regulated by PIDD, which is activated by an as yet unknown signal (Janssens et al, 2005). In response to DSB, NEMO (also known as IKKg) is sumoylated on K277 and K309 by PIASg in a PIDD-dependent fashion, and SUMO-NEMO accumulates in the nucleus (Huang et al, 2003;Janssens et al, 2005;Mabb et al, 2006). Activated ATM phosphorylates SUMO-NEMO to allow its desumoylation and subsequent monoubiquitination on the same lysine residues (Huang et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

et al. 2007

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Cellsres pond to DNA damage in a complex way and the fate of damaged cells depends on the balance between pro-and antiapoptotic signals. This is of crucial importance in cancer as genotoxic stress is implied both in oncogenesis and in classical tumor therapies. p53-induced protein with a death domain (PIDD), initially described as a p53-inducible gene, is one of the molecular switches able to activate a survival or apoptotic program. Two isoforms of PIDD, PIDD ( isoform 1) and LRDD ( isoform 2), have already been reported and we describe here a third isoform. These three isoforms are differentially expressed in tissues and cell lines. Genotoxic stress only affects PIDD isoform 3 mRNA levels, whereas isoforms 1 and 2 mRNA levels remain unchanged. All isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. Isoform 2 counteracts the pro-apoptotic function of isoform 1, whereas isoform 3 enhances it. Thus, the differential splicing of PIDD mRNA leads to the formation of at least three proteins with antagonizing/agonizing functions, thereby regulating cell fate in response to DNA damage

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Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbmentioning

confidence: 98%

Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

et al. 2007

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Role of activated nuclear factor‐κB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck

et al. 2007

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Blockage of NF‐κB by IKKβ‐ or RelA‐siRNA rather than the NF‐κB super‐suppressor IκBα mutant potentiates adriamycin‐induced cytotoxicity in lung cancer cells

Chen

Wang

Bai

et al. 2008

J of Cellular Biochemistry

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Ambiguous roles of genotoxic anticancer therapeutic-induced NF-κB activation in regulating gene expression (activation or suppression) and apoptosis (anti-or pro-apoptosis) have recently been suggested. In order to clarify this controversy and determine the usefulness of NF-κB blockage for sensitizing anticancer therapy, we have systematically investigated the effect of distinct NF-κB-blocking approaches on lung cancer cells' responses to Adriamycin-induced cytotoxicity. The results show that Adriamycin-induced NF-κB activation functions as a transcriptional activator triggering the expression of anti-apoptotic genes. Blocking NF-κB with IKKβ or RelA siRNA substantially sensitized Adriamycin-induced cytotoxicity, suggesting that the NF-κB pathway could be a target for sensitizing lung cancer cells to Adriamycin's anticancer effect. Surprisingly, although it effectively blocks NF-κB activation, the IκBα super-suppressor (IκBαAA) antagonized Adriamycin-induced cell death. Additionally, the induction of death receptor 5 (DR5), which contributes to Adriamycin-induced cytotoxicity, was not affected by NF-κB blockage. Thus, our results suggest that Adriamycin-induced NF-κB is a transcriptional activator that protects lung cancer cells against apoptosis, and IKKβ or RelA siRNA rather than IκBαAA is an appropriate NF-κB blocking approach for sensitizing lung cancer cells to Adriamycin-induced cytotoxicity. KeywordsNF-κB; Adriamycin; siRNA; cytotoxicity; sensitization Genotoxic anticancer therapeutics such as the DNA topoisomerase II inhibitor Adriamycin kill cancer cells mainly by inducing DNA damage that results in apoptosis. On the other hand, DNA damage also activates the transcription factor NF-κB. Because NF-κB activates expression of a number of anti-apoptotic genes, it is generally believed to be a cell survival signal that suppresses apoptosis. Accordingly, it is anticipated that blockage of NF-κB will sensitize cancer cells to anticancer therapeutics, which have been tested in a wide variety of cancers [Janssens and Tschopp, 2006;Wang et al., 2002]. However, NF-κB also upregulates a series of pro-apoptosis genes such as death receptor 5 (DR5), Bax, Fas ligand and p73 [Kikuchi et al., 2006;Shou et al.,. 2002;Singh et al, 2007], thus, a pro-apoptotic role of NF-κB has been proposed Furthermore, a recent finding that genotoxic stress-induced NF-κB activation may function as a transcription suppressor has added more complexity into this [Campbell et al., 2004;Ho et al., 2005;Perkins, 2004]. It is likely that the activation of NF-κB target genes and the cellular outcome in response to DNA damage-induced NF-κB activation are dependent on the cellular context [Janssens and Tschopp, 2006;Wang et al., 2002]. Thus, for improving the anticancer value of Adriamycin, it is important to determine the exact role of NF-κB in Adriamycin-induced apoptosis and to establish appropriate means for manipulating NF-κB in cancer cells.NF-κB is typically a heterodimer consisting of the RelA/p65 and p50 subunits, which is kept i...

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PIDD Mediates NF-κB Activation in Response to DNA Damage

Cited by 302 publications

References 45 publications

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

Role of activated nuclear factor‐κB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck

Blockage of NF‐κB by IKKβ‐ or RelA‐siRNA rather than the NF‐κB super‐suppressor IκBα mutant potentiates adriamycin‐induced cytotoxicity in lung cancer cells

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