Deletion of the N-terminus of IKK{gamma} induces apoptosis in keratinocytes and impairs the AKT/PTEN signaling pathway
- Centro de Investigacion Principe Felipe, Valencia, Av. Autopista del Saler 16, Camino de las Moreras, E-46013, Valencia (Spain)
- Centro de Investigacion Principe Felipe, Valencia, Av. Autopista del Saler 16, Camino de las Moreras, E-46013, Valencia (Spain) and Instituto de Biomedicina de Valencia IBV-CSIC, Jaime Roig 11, E-46010, Valencia (Spain)
The regulatory subunit IKK{gamma}/NEMO is crucial for skin development and function and although devoid of kinase activity, loss of IKK{gamma} function completely abolishes the activation of NF-{kappa}B by all pro-inflammatory cytokines. To inhibit the I{kappa}B kinase (IKK) complex in keratinocytes, we have used a dominant negative approach by generating stable transfectants of an N-terminal deletion of IKK{gamma} (IKK{gamma}-DN97) that uncouples formation of the IKK complex. Expression of this mutant in PB keratinocytes (PB-IKK{gamma}-DN97) delayed growth kinetics, caused morphological changes and dramatically augmented apoptosis even in the absence of pro-apoptotic stimuli, as determined by cell morphology, TUNEL and caspase-3 cleavage. Moreover, in PB-IKK{gamma}-DN97 cells, TNF-{alpha} and IL-1 treatment failed to induce degradation of I{kappa}B{alpha}, phosphorylation of p65 on Ser 536 and nuclear translocation which, consequently, reduced {kappa}B-binding activity. In PB-IKK{gamma}-DN97 cells, accumulation of I{kappa}B{alpha} correlated with a downregulation of AKT activity and an increase of PTEN protein levels whereas pro-apoptotic p53 target genes Bax and Puma were upregulated. These effects were most likely mediated through IKK since coexpression of the wild-type form of IKK{gamma} in keratinocytes partially reversed apoptosis and reduced PTEN expression. Thus, our data suggest a negative cross-talk mechanism involving PTEN and NF-{kappa}B, critical for the anti-apoptotic role of NF-{kappa}B in keratinocytes.
- OSTI ID:
- 20972121
- Journal Information:
- Experimental Cell Research, Vol. 313, Issue 4; Other Information: DOI: 10.1016/j.yexcr.2006.11.009; PII: S0014-4827(06)00480-0; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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