Abstract
In response to DNA damage, p53 and its homolog p73 have a function antagonistic to NF-kappaB in deciding cell fate. Here, we show for the first time that p73, but not p53, is stabilized by physical interaction with nuclear IkappaB kinase (IKK)-alpha to enhance cisplatin (CDDP)-induced apoptosis. CDDP caused a significant increase in the amounts of nuclear IKK-alpha and p73alpha in human osteosarcoma-derived U2OS cells. Ectopic expression of IKK-alpha prolonged the half-life of p73 by inhibiting its ubiquitination and thereby enhancing its transactivation and pro-apoptotic activities. Consistent with these results, small interfering RNA-mediated knockdown of endogenous IKK-alpha inhibited the CDDP-mediated accumulation of p73alpha. The kinase-deficient mutant form of IKK-alpha interacted with p73alpha, but failed to stabilize it. Furthermore, CDDP-mediated accumulation of endogenous p73alpha was not detected in mouse embryonic fibroblasts (MEFs) prepared from IKK-alpha-deficient mice, and CDDP sensitivity was significantly decreased in IKK-alpha-deficient MEFs compared with wild-type MEFs. Thus, our results strongly suggest that the nuclear IKK-alpha-mediated accumulation of p73alpha is one of the novel molecular mechanisms to induce apoptotic cell death in response to CDDP, which may be particularly important in killing tumor cells with p53 mutation.
Highlights
The NF-B signaling pathway is activated by a variety of structurally and functionally unrelated stimuli, including inflammatory cytokines, ionizing radiation, viral and bacterial infection, and oxidative stress
The proteolytic degradation of IB proteins exposes the nuclear localization signal of NF-B and results in translocation of NF-B from the cytoplasm to the nucleus, allowing it to participate in transcriptional regulation of numerous target genes involved in immune responses, inflammatory reactions, cell adhesion, cell proliferation, apoptotic cell death, and other cellular processes
Like p53, endogenous p73 becomes stabilized as well as activated in cells exposed to certain genotoxic stimuli, including ␥-irradiation and cisplatin (CDDP), and contributes to an apoptotic response to DNA damage [15,16,17]. p73 is expressed as multiple isoforms that differ at their N and C termini, arising from alternative splicing and promoter usage
Summary
The NF-B signaling pathway is activated by a variety of structurally and functionally unrelated stimuli, including inflammatory cytokines, ionizing radiation, viral and bacterial infection, and oxidative stress (reviewed in Refs. 1 and 2). Treatment, whereas a marked increase in the expression level of IKK-␥ mRNA was detected in a time-dependent manner in response to CDDP (Fig. 1C).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
