Identification of a novel pro-apopotic function of NF-kappaB in the DNA damage response.
Identification of a novel pro-apopotic function of NF-kappaB in the DNA damage response.
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DOI：
10.1111/j.1582-4934.2009.00888.x
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发表时间：
2009-10
影响因子：
5.3
通讯作者：
Fulda S
中科院分区：
文献类型：
--
作者：
Karl S;Pritschow Y;Volcic M;Häcker S;Baumann B;Wiesmüller L;Debatin KM;Fulda S
作为细胞应激反应的一部分，核因子-κB被破坏dna的抗癌药物激活。然而，药物诱导的NF-κB激活的后果仍然只有部分了解。为了研究NF-κB对细胞DNA损伤反应的影响，我们设计了稳定表达突变型IκBα超抑制因子(IκBα-SR)的胶质母细胞瘤细胞来阻断NF-κB的激活。在这里，我们确定了在胶质母细胞瘤细胞的κ损伤反应中，核因子-DNAB的一种新的促凋亡功能。插入脱氧核糖核酸并抑制拓扑异构酶II的化疗药物，如阿霉素、柔红霉素和米托蒽醌，可在诱导细胞死亡之前刺激核因子-κB的DNA结合和转录活性。重要的是，通过IκBκBα-SR或针对p65的RNA干扰而特异性地抑制药物诱导的NF-RNA B的激活，可以显著减少阿霉素、柔红霉素或米托蒽醌治疗后的细胞凋亡。与持续治疗相比，NF-κB具有促凋亡作用，尤其是在脉冲药物暴露后，这表明在最初的κ损伤后的恢复期，NF-DNAB的作用变得重要。机制研究表明，抑制NF-κB不会改变阿霉素的摄取和外排或细胞周期的改变。核糖核酸干扰对P53基因沉默的研究表明，NF-κB以非依赖于P53的方式促进药物诱导的细胞凋亡。有趣的是，药物介导的NF-κB激活在诱导细胞凋亡之前会导致DNA损伤的显著增加。通过证明在κ嵌入物的脉冲治疗下，NF-κB促进了DNA损伤的形成和细胞的凋亡，我们的发现为控制神经胶质母细胞瘤中的DNA损伤反应提供了新的见解。
NF-κB is activated by DNA-damaging anticancer drugs as part of the cellular stress response. However, the consequences of drug-induced NF-κB activation are still only partly understood. To investigate the impact of NF-κB on the cell’s response to DNA damage, we engineered glioblastoma cells that stably express mutant IκBα superrepressor (IκBα-SR) to block NF-κB activation. Here, we identify a novel pro-apoptotic function of NF-κB in the DNA damage response in glioblastoma cells. Chemotherapeutic drugs that intercalate into DNA and inhibit topoisomerase II such as Doxorubicin, Daunorubicin and Mitoxantrone stimulate NF-κB DNA binding and transcriptional activity prior to induction of cell death. Importantly, specific inhibition of drug-induced NF-κB activation by IκBα-SR or RNA interference against p65 significantly reduces apoptosis upon treatment with Doxorubicin, Daunorubicin or Mitoxantrone. NF-κB exerts this pro-apoptotic function especially after pulse drug exposure as compared to continuous treatment indicating that the contribution of NF-κB becomes relevant during the recovery phase following the initial DNA damage. Mechanistic studies show that NF-κB inhibition does not alter Doxorubicin uptake and efflux or cell cycle alterations. Genetic silencing of p53 by RNA interference reveals that NF-κB promotes drug-induced apoptosis in a p53-independent manner. Intriguingly, drug-mediated NF-κB activation results in a significant increase in DNA damage prior to the induction of apoptosis. By demonstrating that NF-κB promotes DNA damage formation and apoptosis upon pulse treatment with DNA intercalators, our findings provide novel insights into the control of the DNA damage response by NF-κB in glioblastoma.
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影响因子：
7.2
作者：
Hewson, QDC;Lovat, PE;Redfern, CRF
通讯作者：
Redfern, CRF
影响因子：
16
作者：
Campbell, KJ;Rocha, S;Perkins, ND
通讯作者：
Perkins, ND
影响因子：
4.8
作者：
Bian, X;McAllister-Lucas, LM;Opipari, AW
通讯作者：
Opipari, AW
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth
影响因子：
56.9
作者：
Brummelkamp, TR;Bernards, R;Agami, R
通讯作者：
Agami, R