Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

Stróżyk, Elwira; Pöppelmann, Birgit; Schwarz, Thomas; Kulms, Dagmar

doi:10.1038/sj.onc.1209655

Cited by 55 publications

(49 citation statements)

References 38 publications

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“…22,24 According to our findings, UVB-induced apoptosis of keratinocytes and epithelial cells is significantly enhanced upon co-treatment with IL-1 in vitro. 7,8,25 Correspondingly, UVB-induced apoptosis of keratinocytes in vivo may be facilitated by concomitant IL-1 signals from neighbouring cells. We therefore propose that the signal cross talk at the level of keratinocytes is of patho/ physiological relevance in differential skin responses to UVB.…”

Section: Discussionmentioning

confidence: 99%

“…Following stimulation cells were harvested and nuclear extracts were generated as described before. 25 EMSA was performed using an NF-kB consensus oligonucleotide (sc-2505; Santa Cruz). For supershift assays the following antibodies recognizing p65, p50, p52, c-Rel and RelB were used: sc-109X, sc-7178X, sc-7386, sc-70X, sc-226X (Santa Cruz).…”

Section: Discussionmentioning

confidence: 99%

“…Transfection of cells with siRNA (MWG) was carried out in Lipofectamin2000 (Invitrogen). For semiquantitative RT-PCR, cDNA was generated as described before 25 using the RedTaq system (Sigma).…”

Section: Discussionmentioning

confidence: 99%

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Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor

et al. 2008

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Although nuclear factor-jB (NF-jB) usually exerts anti-apoptotic activity, upon activation by interleukin-1 (IL-1) it enhances ultraviolet-B radiation (UVB)-induced apoptosis. This paradoxical effect is associated with NF-jB-dependent pronounced secretion of tumour necrosis factor-a (TNF) which activates TNF-R1 in an autocrine fashion to enhance UVB-induced apoptosis. We demonstrate that sustained TNF transcription in UVB þ IL-1-treated cells involves complete abrogation of the negative feedback loop of NF-jB preventing IjBa resynthesis, hence allowing uncontrolled NF-jB activity. We show that IjBa is not transcriptionally inhibited but resynthesized protein is immediately marked for degradation due to persistent inhibitor of jB kinaseb (IKKb) activity. Continuous IKKb phosphorylation and activation is caused by UVB-mediated inhibition of the phosphatase PP2A. This study demonstrates that the cellular response to different NF-jB activators may be converted to the opposite reaction when both stimuli act in concert. Our data shed new light on the significance of negative feedback regulation of NF-jB and identifies PP2A as the key regulator of this process. The transcription factor nuclear factor-kB (NF-kB) is involved in many cellular responses. It comprises five proteins: p50/ p105, p52/p100, p65, c-Rel and RelB that exist as homo-and heterodimers, p65/p50 being the most abundant form. In unstimulated cells, NF-kB is sequestered in the cytoplasm through interaction with the inhibitory protein IkBa that masks its nuclear localization signal. 1 NF-kB (p65/p50) is mostly activated by pro-inflammatory mediators, including tumour necrosis factor-a (TNF), interleukin-1 (IL-1) or LPS. Activated receptors mediate activation of a multi subunit inhibitor of kB kinase (IKK) complex consisting of IKKa, -b and -g. Activated IKK acts through phosphorylation of IKKb at Ser177/181, subsequently catalysing phosphorylation of inhibitor of kBa (IkBa) at Ser32/36, leading to its polyubiquitination and proteasomal degradation. Released NF-kB translocates into the nucleus to activate responsive genes, among these the one encoding IkBa. 2 Nuclear export of resynthesized IkBa is more potent than import, allowing cytosolic localization of the inactive complex, thus creating a negative feedback loop. 3 As NF-kB serves many different functions, tight regulation by the negative feedback loop is crucial. Only highly controlled and transient expression of NF-kB-driven genes ensures proper function. Uncontrolled NF-kB activity is linked to transformation, proliferation, suppression of apoptosis and metastasis. 4,5 Thus, strategies interfering with signalling pathways activating NF-kB have become major targets for anticancer interventions. 6 We have previously shown that stimulus-dependent activation of NF-kB can result in completely opposite effects. Stimulation with IL-1 protects keratinocytes and epithelial cells from cytotoxic effects of death ligands in an NF-kB-dependent manner by upregulation of anti-apoptotic cFLIP and cIAPs. 7 In contr...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor

et al. 2008

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“…New data have revealed that the ability of different topoisomerase II inhibitors to promote transcriptional repression by NF-kB depends on their ability to intercalate into DNA, but not on their ability to inhibit topoisomerase II or on production of oxygen-free radicals (Campbell et al, 2006a). Others found that certain types of DNA lesions are correlated with production of TNFa and that this influences the outcome of the cells (Strozyk et al, 2006). Although much remains to be understood at the molecular level, these findings begin to elucidate why atypical activators like etoposide promote RelA's transcriptional and antiapoptotic activity while others repress it.…”

Section: Mechanisms Implicated In Nf-kb's Proapoptotic Activitymentioning

confidence: 99%

Current insights into the regulation of programmed cell death by NF-κB

et al. 2006

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“…Following stimulation cells were harvested and nuclear proteins extracted as described before [24]. The NFB consensus oligo nucleotide (sc-2505; Santa Cruz) was end-labeled using M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 8 …”

Section: Electro Mobility Shift Assay (Emsa)mentioning

confidence: 99%

Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A

Barisic

Schmidt

Walczak

et al. 2010

Biochemical Pharmacology

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Activation status of Tyr-kinase Src as well as of the transcription factor NFB is a decisive criterion for the onset of cancer and in conveying radio-resistance. While the activation status of Src is Tyr-phosphorylation dependent, NFB activation requires Ser phosphorylation of its cytosolic inhibitor, IBSince constitutive NFB activation was linked to tumor maintenance, its tight regulation is mandatory.We provide evidence that inhibition of pan-Try phosphatase activity by orthovanadate is translated via Src to inhibition of Ser phosphatase PP2A, thereby changing the physiologic response of the cell. In particular we unravelled a new sequence of molecular interactions linking initial activating Tyr416 phosphorylation of Src not to Tyr42-dependent phosphorylation and degradation of IB, but to sustained Ser177/181 phosphorylation of IB kinase IKK following IL-1 stimulation. Consequently, sustained IKK activation provides for chronic canonical IB degradation, thereby eliciting constitutive NFB activation. As the critical translator of Tyr to Ser phosphorylation we identified Ser/Thr phosphatase PP2A. We show that the catalytic subunit PP2Ac serves as a Src substrate with Tyr307 phosphorylation leading to its catalytic inhibition. Additionally to the known survival pathways triggered by Src, Src-mediated canonical and persistent NFB activation may fortify its tumorigenic effects.

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Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

Cited by 55 publications

References 38 publications

Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor

Identification of PP2A as a crucial regulator of the NF-κB feedback loop: its inhibition by UVB turns NF-κB into a pro-apoptotic factor

Current insights into the regulation of programmed cell death by NF-κB

Tyrosine phosphatase inhibition triggers sustained canonical serine-dependent NFκB activation via Src-dependent blockade of PP2A

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