Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 17, Pages 16843-16850Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M410119200
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- NCI NIH HHS [CA 097159, CA 78778] Funding Source: Medline
- PHS HHS [PA-98-029] Funding Source: Medline
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RelA, the p65 subunit of NF-kappa B transcription factors, plays a key role in regulation of antiapoptotic and proapoptotic responses. However, the downstream target genes regulated by RelA-NF-kappa B in the initiation of proapoptotic signaling were not identified. We previously showed that RelA-NF-kappa B functioned as a proapoptotic factor by activating the p53-signaling pathway in response to doxycycline-induced superoxide. In the present study, we demonstrate that the ability of doxycycline/ superoxide to induce expression of polo-like kinase 3 (Plk3) depends on NF-kappa B activity. We identified a kappa B binding site in the promoter of Plk3, and this kappa B site is directly involved in its induction by the RelA-NF-kappa B complex. Plk3 formed a complex with p53 and was involved in the phosphorylation of p53 on Ser-20 in response to superoxide. Inhibition of Plk3 expression by Plk3 small interfering RNA suppressed the doxycycline/ superoxide-mediated apoptosis. Overexpression of wildtype Plk3 in HCT116 p53(+/+) cells induced rapid apoptosis, whereas overexpression of wild-type Plk3 in HCT116 p53(-/-) cells and the kinase-defective mutant Plk3(K91R) in p53(-/-) cells induced delayed onset of apoptosis. Furthermore, mutagenesis of Plk3 showed that the N-terminal domain ( amino acids 1 - 26) is essential for the induction of delay onset of apoptosis. These data show that Plk3 is a RelA-NF-kappa B-regulated gene that induces apoptosis in both p53-dependent and - independent signaling pathways, suggesting a possible mechanism for RelA-NF-kappa B-regulated proapoptotic responses.
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