Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 24 February 2006:
Vol. 311. no. 5764, pp. 1141 - 1146
DOI: 10.1126/science.1121513
Prev | Table of Contents | Next

Reports

Molecular Linkage Between the Kinase ATM and NF-{kappa}B Signaling in Response to Genotoxic Stimuli

Zhao-Hui Wu, Yuling Shi, Randal S. Tibbetts, Shigeki Miyamoto*

The transcription factor NF-{kappa}B modulates apoptotic responses induced by genotoxic stress. We show that NF-{kappa}B essential modulator (NEMO), the regulatory subunit of I{kappa}B kinase (IKK) (which phosphorylates the NF-{kappa}B inhibitor I{kappa}B), associates with activated ataxia telangiectasia mutated (ATM) after the induction of DNA double-strand breaks. ATM phosphorylates serine-85 of NEMO to promote its ubiquitin-dependent nuclear export. ATM is also exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS). Thus, regulated nuclear shuttling of NEMO links two signaling kinases, ATM and IKK, to activate NF-{kappa}B by genotoxic signals.

Department of Pharmacology, University of Wisconsin–Madison, 301 SMI, 1300 University Avenue, Madison, WI 53706, USA.

* To whom correspondence should be addressed. E-mail: smiyamot{at}wisc.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Ro52-mediated Monoubiquitination of IKK{beta} Down-regulates NF-{kappa}B Signalling.
K. Wada, M. Niida, M. Tanaka, and T. Kamitani (2009)
J. Biochem. 146, 821-832
   Abstract »    Full Text »    PDF »
NEMO-binding Domains of Both IKK{alpha} and IKK{beta} Regulate I{kappa}B Kinase Complex Assembly and Classical NF-{kappa}B Activation.
L. A. Solt, L. A. Madge, and M. J. May (2009)
J. Biol. Chem. 284, 27596-27608
   Abstract »    Full Text »    PDF »
Inhibition of Ataxia Telangiectasia Mutated Kinase Activity Enhances TRAIL-Mediated Apoptosis in Human Melanoma Cells.
V. N. Ivanov, H. Zhou, M. A. Partridge, and T. K. Hei (2009)
Cancer Res. 69, 3510-3519
   Abstract »    Full Text »    PDF »
cIAP1, cIAP2, and XIAP Act Cooperatively via Nonredundant Pathways to Regulate Genotoxic Stress-Induced Nuclear Factor-{kappa}B Activation.
H.-S. Jin, D.-H. Lee, D.-H. Kim, J.-H. Chung, S.-J. Lee, and T. H. Lee (2009)
Cancer Res. 69, 1782-1791
   Abstract »    Full Text »    PDF »
Aberrant activation of stress-response pathways leads to TNF-{alpha} oversecretion in Fanconi anemia.
D. Briot, G. Mace-Aime, F. Subra, and F. Rosselli (2008)
Blood 111, 1913-1923
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 68 in the I{kappa}B Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-{alpha}-induced NF-{kappa}B Activity.
L. Palkowitsch, J. Leidner, S. Ghosh, and R. B. Marienfeld (2008)
J. Biol. Chem. 283, 76-86
   Abstract »    Full Text »    PDF »
Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase.
B. A. Olofsson, C. M. Kelly, J. Kim, S. M. Hornsby, and J. Azizkhan-Clifford (2007)
Mol. Cancer Res. 5, 1319-1330
   Abstract »    Full Text »    PDF »
Novel Mechanism whereby Nuclear Factor {kappa}B Mediates DNA Damage Repair through Regulation of O6-Methylguanine-DNA-Methyltransferase.
I. Lavon, D. Fuchs, D. Zrihan, G. Efroni, B. Zelikovitch, Y. Fellig, and T. Siegal (2007)
Cancer Res. 67, 8952-8959
   Abstract »    Full Text »    PDF »
Beyond I{kappa}Bs: alternative regulation of NF-{kappa}B activity.
M. Neumann and M. Naumann (2007)
FASEB J 21, 2642-2654
   Abstract »    Full Text »    PDF »
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis.
C. Cerboni, A. Zingoni, M. Cippitelli, M. Piccoli, L. Frati, and A. Santoni (2007)
Blood 110, 606-615
   Abstract »    Full Text »    PDF »
Hyperthermia Activates a Subset of Ataxia-Telangiectasia Mutated Effectors Independent of DNA Strand Breaks and Heat Shock Protein 70 Status.
C. R. Hunt, R. K. Pandita, A. Laszlo, R. Higashikubo, M. Agarwal, T. Kitamura, A. Gupta, N. Rief, N. Horikoshi, R. Baskaran, et al. (2007)
Cancer Res. 67, 3010-3017
   Abstract »    Full Text »    PDF »
Identification of Carboxyl-terminal MCM3 Phosphorylation Sites Using Polyreactive Phosphospecific Antibodies.
Y. Shi, G. E. Dodson, P. S. Mukhopadhyay, N. P. Shanware, A. T. Trinh, and R. S. Tibbetts (2007)
J. Biol. Chem. 282, 9236-9243
   Abstract »    Full Text »    PDF »
Radiation-induced cell signaling: inside-out and outside-in.
K. Valerie, A. Yacoub, M. P. Hagan, D. T. Curiel, P. B. Fisher, S. Grant, and P. Dent (2007)
Mol. Cancer Ther. 6, 789-801
   Abstract »    Full Text »    PDF »
Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli.
C. M. Berchtold, Z.-H. Wu, T. T. Huang, and S. Miyamoto (2007)
Mol. Cell. Biol. 27, 497-509
   Abstract »    Full Text »    PDF »
Deoxycholate induces mitochondrial oxidative stress and activates NF-{kappa}B through multiple mechanisms in HCT-116 colon epithelial cells.
C.M. Payne, C. Weber, C. Crowley-Skillicorn, K. Dvorak, H. Bernstein, C. Bernstein, H. Holubec, B. Dvorakova, and H. Garewal (2007)
Carcinogenesis 28, 215-222
   Abstract »    Full Text »    PDF »
Dimerization of the I{kappa}B Kinase-Binding Domain of NEMO Is Required for Tumor Necrosis Factor Alpha-Induced NF-{kappa}B Activity.
R. B. Marienfeld, L. Palkowitsch, and S. Ghosh (2006)
Mol. Cell. Biol. 26, 9209-9219
   Abstract »    Full Text »    PDF »
Nuclear Factor-{kappa}B p65 Inhibits Mitogen-Activated Protein Kinase Signaling Pathway in Radioresistant Breast Cancer Cells.
K. M. Ahmed, S. Dong, M. Fan, and J. J. Li (2006)
Mol. Cancer Res. 4, 945-955
   Abstract »    Full Text »    PDF »
Loss of Ikkbeta Promotes Migration and Proliferation of Mouse Embryo Fibroblast Cells.
F. Chen, Y. Lu, V. Castranova, Z. Li, and M. Karin (2006)
J. Biol. Chem. 281, 37142-37149
   Abstract »    Full Text »    PDF »
Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-{kappa}B Inactivation..
D.-S. Kim, S.-S. Park, B.-H. Nam, I.-H. Kim, and S.-Y. Kim (2006)
Cancer Res. 66, 10936-10943
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)