Transcriptional regulation of APAF1 by KAISO and p53

Abstract

KAISO, a POK family protein, has been conflictingly characterized as both a tumor suppressor and an oncoprotein. Here, KAISO was induced by the DNA-damaging agent etoposide to enhance apoptosis in a p53-dependent manner via upregulation of APAF1, the core molecule of the apoptosome. Previously, we found that p53 interacts with KAISO, which in turn modulates p300 acetylation of p53 lysine residues. Moreover, p53 activates APAF1 transcription, and p53 binding is further enhanced by KAISO at the APAF1 promoter distal p53 response element (p53RE#1, bp, -765 ~ -739). Interestingly, an NF-κB response element, located close to p53RE#1, bound NF-κB to transcriptionally repress APAF1 by disrupting interactions between KAISO and p53 within a p53-KAISO-p300 activating complex, formed upon exposure to genotoxic stress. Subcellular fractionation also revealed that ectopic expression of the NF-κB family member RelA/p65 led to depletion of KAISO in the nucleus and predominant KAISO localization to the cytoplasm. Thus, while KAISO enhances p53-dependent apoptosis by activating or enhancing APAF1 gene expression, RelA/p65 decreases apoptosis by blocking interaction between KAISO and p53.