This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kawai, H.
Right arrow Articles by Yuan, Z.-M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kawai, H.
Right arrow Articles by Yuan, Z.-M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2002, p. 6079-6088, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6079-6088.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inactivation of NF-{kappa}B-Dependent Cell Survival, a Novel Mechanism for the Proapoptotic Function of c-Abl

Hidehiko Kawai, Linghu Nie, and Zhi-Min Yuan*

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115

Received 17 January 2002/ Returned for modification 21 February 2002/ Accepted 4 June 2002

Using a system that expresses a constitutively kinase-active c-Abl protein [c-Abl(KA)], we identified the protein I{kappa}B{alpha} as a novel substrate of c-Abl. This kinase-substrate relationship is not only confirmed at the level of endogenous proteins but is also supported by a physical interaction between the two proteins. Interestingly, the association of c-Abl with I{kappa}B{alpha}, which is detectable in the form of nonphosphorylated proteins, is remarkably enhanced by an inducible binding of tyrosine-phosphorylated I{kappa}B{alpha} to the c-Abl SH2 domain. In contrast to the serine 32/34 phosphorylation that triggers ubiquitination and degradation of I{kappa}B{alpha}, c-Abl-mediated phosphorylation at tyrosine 305 is associated with an increase of the I{kappa}B{alpha} protein stability. Significantly, this activity is not shared by the oncogenic Bcr-Abl, because it is unique to the nuclear c-Abl. We also demonstrate that c-Abl targets the nuclear subpopulation of I{kappa}B{alpha} for phosphorylation and induces it to accumulate in the nucleus. As a consequence, NF-{kappa}B transcription activity is abolished, leading to an increased cellular sensitivity to the induction of apoptosis. The functional importance of c-Abl-mediated I{kappa}B{alpha} phosphorylation is highlighted by a loss of response of the I{kappa}B{alpha}(Y305F) protein to c-Abl-mediated regulation. Using cells expressing the c-Abl(KA) protein under the control of an inducible promoter, we demonstrate inactivation of the NF-{kappa}B-dependent cell survival pathway as one of the mechanisms for c-Abl-mediated apoptosis.

* Corresponding author. Mailing address: Department of Cancer Cell Biology (Bldg. 1, Room 209), Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Phone: (617) 432-0763. Fax: (617) 432-0107. E-mail: zyuan{at}hsph.Harvard.edu.

Molecular and Cellular Biology, September 2002, p. 6079-6088, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6079-6088.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Liberatore, R. A., Goff, S. P., Nunes, I. (2009). NF-{kappa}B activity is constitutively elevated in c-Abl null fibroblasts. Proc. Natl. Acad. Sci. USA 106: 17823-17828 [Abstract] [Full Text]  
  • Hagerkvist, R., Sandler, S., Mokhtari, D., Welsh, N. (2007). Amelioration of diabetes by imatinib mesylate (Gleevec(R)): role of {beta}-cell NF-{kappa}B activation and anti-apoptotic preconditioning. FASEB J. 21: 618-628 [Abstract] [Full Text]  
  • Kamath, R., Jiang, Z., Sun, G., Yalowich, J. C., Baskaran, R. (2007). c-Abl Kinase Regulates Curcumin-Induced Cell Death through Activation of c-Jun N-Terminal Kinase. Mol. Pharmacol. 71: 61-72 [Abstract] [Full Text]  
  • Stuart, J. R., Gonzalez, F. H., Kawai, H., Yuan, Z.-M. (2006). c-Abl Interacts with the WAVE2 Signaling Complex to Induce Membrane Ruffling and Cell Spreading. J. Biol. Chem. 281: 31290-31297 [Abstract] [Full Text]  
  • Peng, Y., Power, M. R., Li, B., Lin, T.-J. (2005). Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-I{kappa}B-NF-{kappa}B pathway in IgE-dependent mast cell activation. J. Leukoc. Biol. 77: 975-983 [Abstract] [Full Text]  
  • Wu, Y., Adam, S., Hamann, L., Heine, H., Ulmer, A. J., Buwitt-Beckmann, U., Stamme, C. (2004). Accumulation of Inhibitory {kappa}B-{alpha} as a Mechanism Contributing to the Anti-Inflammatory Effects of Surfactant Protein-A. Am. J. Respir. Cell Mol. Bio. 31: 587-594 [Abstract] [Full Text]  
  • Kawai, H., Wiederschain, D., Kitao, H., Stuart, J., Tsai, K. K. C., Yuan, Z.-M. (2003). DNA Damage-induced MDMX Degradation Is Mediated by MDM2. J. Biol. Chem. 278: 45946-45953 [Abstract] [Full Text]  
  • Tsai, K. K. C., Yuan, Z.-M. (2003). c-Abl Stabilizes p73 by a Phosphorylation-augmented Interaction. Cancer Res. 63: 3418-3424 [Abstract] [Full Text]  
  • Derrien, A., Zheng, B., Osterhout, J. L., Ma, Y.-C., Milligan, G., Farquhar, M. G., Druey, K. M. (2003). Src-mediated RGS16 Tyrosine Phosphorylation Promotes RGS16 Stability. J. Biol. Chem. 278: 16107-16116 [Abstract] [Full Text]  
  • Kitao, H., Yuan, Z.-M. (2002). Regulation of Ionizing Radiation-induced Rad52 Nuclear Foci Formation by c-Abl-mediated Phosphorylation. J. Biol. Chem. 277: 48944-48948 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»