p53 Mutations and Inflammation-Associated Cancer Are Linked through TNF Signaling

Abstract

In this issue, Di Minin et al. (2014) link mutant p53 and chronic inflammation to tumorigenic progression via TNF signaling. Mirtp53 interacts with the tumor suppressor DAB2IP in the cytoplasm, and induces a TNF-dependent transcriptional profile via NF-kB and JNK.

Mutations in p53 are the most common events in human cancers and have long been a focus of intensive research. Though debatable at the beginning, the existence of novel gain-of-function by specific p53 mutants (mutp53) has become more and more acknowledged in recent years, as such mutants are reported to be directly involved in various oncogenic processes (Muller and Vousden, 2014, The p53 IARC website -http://p53.iarc.fr/). Despite its incapacity to bind to the chromatin over the consensus p53 responsive elements, mutp53 is able to interact with many partners. Enhanced invasion and motility, TGF-β regulation and genomic instability are among the modes-of-action by which different mutants were reported to drive cancerous effects (Rivlin et al., 2011, Jackson and Lozano, 2013). It is, therefore, perhaps not surprising that such mutations might also play a significant role in another hallmark of tumorigenesis: chronic tissue inflammation. In the current issue of Molecular Cell, Di Minin and colleagues (Di Minin et al., 2014) shed light on this profound connection by tackling the complicated cross-talk through which specific p53 mutants continuously fuel pro-inflammatory pathways, eventually exacerbating carcinogenesis and tumor progression.

Di Minin and colleagues stimulated transformed and non-transformed cells from various origins with pro-inflammatory cytokines, including TNF-α and performed invasion assays. They discovered that mutp53 drives tumor progression by increasing cell invasion in response to TNF-α. They also found that mutp53 coordinately modulates TNF-dependent activation of both NF-kB and JNK pathways, corroborating our recent findings on the connection between mutp53 and these pathways (Cooks et al., 2013). Di Minin et al. then attempted to nail down the molecular mechanism through which cells that harbor mutp53 might profit from intensified inflammatory conditions. They screened for potential candidates using gene expression analysis of TNF-α stimulated cells with or without mutp53 silencing, and chose to focus on the tumor suppressor DAB2IP. DAB2IP is known to promote activation of ASK1/JNK and inhibit activation of NF-kB in response to TNF-α (Zhang et al., 2004). DAB2IP is also a cytosolic protein, thus the mutp53-DAB2IP interaction in the cytoplasm further expands the conceptual dogma claiming that nuclear activities of mutp53 are fostering other transcription factors via chromatin remodeling. The authors show that binding of mutp53 to DAB2IP is crucial for the invasive phenotype of cancer cells exposed to inflammation both in vitro and in vivo. By depriving any nuclear signals from mutp53 the authors were able to preserve the pro-tumoral phenotype, supporting the fact that protein-protein interactions occurring outside the nucleus are included in the mutp53 repertoire.

Supporting the relevance of this finding in vivo, the authors mined publically available clinical data sets and found an upregulation of specific TNF-α inducible gene signature in a subtype of breast cancer typed with mutp53. Interestingly, this specific signature, which was in-line with the findings displayed throughout the study, actually correlated with better survival rates. This is another indication that the p53 pathway shares a highly intricate interplay with the inflammatory milieu. On top of the wild-type p53 form there are also 13 different isoforms due to alternative splicing and various transcription start sites, additional family members like p63/p73 as well as the mutants themselves, hence, the interaction between the p53 pathway and different inflammatory conditions might yield a variety of responses. (Cooks et al., 2014, Khoury and Bourdon, 2010).

The study of Di Minin and collaborators is another major step on the way to characterize the conditions at which several p53 mutants endow cellular functions leading to clonal selection and tumorigenesis. While previous studies labeled mutp53 as the initiator of inflammation-associated cancer, the authors herein highlight the gain-of-function effects as an oncogenic promoter rather than a preliminary stage effector. On that note, the time frame used in the experimental design for TNF-α stimulation is presumably crucial for the outcome of the NF-kB activation pattern. Importantly, in such a sensitive system, translating doses, exposure periods and cell types to the microenvironmental interaction inside a tissue is challenging, particularly when the stimulation is channeled via NF-kB which coordinates and distributes a plethora of different signals and phenotypes. It is therefore likely that the set of genes upregulated in response to the TNF-α treatment will vary considerably with time and concentration.

By strengthening the gain-of-function paradigm, this study promotes the next stage in the mutp53 field. TP53 mutations are variable and might give rise to different proteins that may share many structural characteristics but also vary significantly. Furthermore, the mutational spectrum of TP53 is very much dependent on the organ, the tumor type and the carcinogen involved. It is most likely that certain mutants will thrive under chronic conditions of inflammation while others will have no effect. To take this even further, it is likely that different p53 gain of function mutations could collaborate with a specific subtype of the inflammatory arm distinguished by typical immune cell infiltrate, mediating cytokines and molecular pathways involved. Research efforts in this area might help determine the inflammatory responses driving tumorigenesis in specific mutp53 backgrounds, eventually paving the way for powerful prognostic tools (Olivier et al., 2006, Robles and Harris, 2010).

In sum, the findings of DiMinin et al. reinforce that TNF signaling plays a central role in the connection between mutp53 and major factors affecting the inflamed tissue such as NF-kB and JNK. This cross-talk, affected by the interaction of mutp53 with the tumor suppressor DAB2IB in the cytoplasm, contributes to tumori genic effects translated into increased invasion (Figure 1). This study is a cardinal support to the perception suggesting that the complex interplay between the p53 and the NF-kB pathways should be addressed more intensively. While this interaction may be context-dependent, deciphering it will hold the key to many prognostic and therapeutic approaches.

Figure 1. Mutp53 Facilitates TNF Signaling by Interacting with DAB2IP in the Cytoplasm.

A cytoplasmic interaction between mutp53 and DAB2IP prevents the repression of TNF signaling, thus activating NF-kB resulting with an invasion promoting transcriptional profile.