Abstract
An intriguing biological question relating to cell signaling is how the inflammatory mediator NF-kB and the tumour suppressor protein p53 can be induced by similar triggers, like DNA damage or infection, yet have seemingly opposing or sometimes cooperative biological functions. For example, the NF-κB subunit RelA/p65 has been shown to inhibit apoptosis, whereas p53 induces apoptosis. One potential explanation may be their co-regulation by common cellular factors: inhibitor of Apoptosis Stimulating p53 Protein (iASPP) is one such common regulator of both RelA/p65 and p53. Here we show that iASPP is a novel substrate of caspases in response to apoptotic stimuli. Caspase cleaves the N-terminal region of iASPP at SSLD294 resulting in a prominent 80kDa fragment of iASPP. This caspase cleavage site is conserved in various species from zebrafish to Homo sapiens. The 80kDa fragment of iASPP translocates from the cytoplasm to the nucleus via the RaDAR nuclear import pathway, independent of p53. The 80kDa iASPP fragment can bind and inhibit p53 or RelA/p65 more efficiently than full-length iASPP. Overall, these data reveal a potential novel regulation of p53 and RelA/p65 activities in response to apoptotic stimuli.
Highlights
Many signaling proteins seem to have opposing and/or cooperative biological functions
To investigate if inhibitor of Apoptosis Stimulating p53 Protein (iASPP) could be a potential substrate of caspase during the apoptotic response, we used an anti-Fas antibody to trigger apoptosis in human lymphoid tumour CEM cells that contain constitutively activated RelA/p65 and mutant p53 [31]
Quantification showed that changes in the levels of the 80kDa fragment of iASPP were associated with similar changes in cleaved caspase-3 levels (Supplementary Figure S1E-H), suggesting that caspase-3 might be one of the caspases responsible for the generation of the 80kDa iASPP fragment
Summary
Many signaling proteins seem to have opposing and/or cooperative biological functions. One example is the DNA damage- or infection-induced expression of the tumour suppressor p53 and the inflammatory mediator. Alterations in gene expression mediated by these transcription factors often results in opposing cellular outcomes: activation of p53 often leads to cell cycle arrest or apoptosis [1], whereas RelA/p65 activation generally induces pro-proliferative and anti-apoptotic signaling. Several studies have reported cooperative effects between p53 and RelA/p65 signaling pathways in regulating apoptosis. RelA/p65 activation mediates p53-dependent apoptosis in SAOS2 cells [3], and p53-dependent RelA/p65 activation is required for doxorubicin and etoposide-induced cell death in neuroblastoma cells [4]. A major question is how p53 and RelA/p65 signaling is intertwined, during the apoptotic response
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