Cancer is a deadly disease that continues to pose a major challenge to global healthcare systems. It arises when some cells acquire mutations that allow them to grow and divide uncontrollably. A key player for preventing this uncontrolled cell growth is the protein p53, which binds to DNA and regulates the activities of genes that determine whether a cell should grow, divide, or die.

Mutations in the DNA-binding domain of p53 can hinder its ability to regulate gene activity, thereby contributing to cancer. Additionally, shorter versions of p53 – known as p53 isoforms – can accumulate in the cell and coexist with the normal full-length protein. These isoforms sometimes lack critical components of the protein, whilst retaining other properties. For example, two p53 isoforms – called ∆133p53α and ∆160p53α – are missing parts of the DNA-binding domain but can still bind to full-length p53 protein. Here, Zhao, Punga and Sanyal used biochemical and cell biology approaches to investigate how the ∆133p53α and ∆160p53α isoforms affect the activity of full-length p53.

The team found that both isoforms can bind to full-length p53 protein and form tetramers, large molecules made up of four p53 sub-units. In addition, they found that the ∆133p53α and ∆160p53α isoforms can form aggregates with full-length p53. As a result, full-length p53 protein gets sequestered within these aggregates, which prevents them from binding to DNA and carrying out their role in gene expression and cell-death regulation.

These findings open up new avenues for cancer research, particularly in cancer patients who have truncated isoforms of the p53 protein. Developing new therapies that prevent shorter and normal full-length p53 protein from forming irregular aggregates may have the potential to prevent, or slow, cancer progression in these patients.

The tumor suppressor protein p53 is an essential transcription activator protein modulating the expression of multiple target genes. By regulating various cellular processes such as cell cycle arrest, apoptosis, senescence, DNA repair, and angiogenesis, p53 prevents cancer development (Levine and Oren, 2009; Vogelstein et al., 2000). The intricate p53 pathway is stimulated by various stress stimuli, including DNA damage and oncogene activation, which lead to the stabilization and activation of the p53 protein (Pflaum et al., 2014). Stabilized p53 acts as a transcription activator protein as it can directly bind to its response elements (REs) and recruit different transcription co-activator proteins at various gene promoters (Sullivan et al., 2018). One of the best-known p53 targets is the p21 (also known as CIP1, WAF1) gene promoter, which contains two p53REs and is efficiently activated by the p53 protein (el-Deiry et al., 1993; Macleod et al., 1995). The encoded p21 protein blocks cell cycle progression and thereby executes tumor suppressor activity of the p53 protein (Indeglia and Murphy, 2024; Shamloo and Usluer, 2019).

The TP53 gene produces at least 12 distinct p53 isoforms: p53 (α, β, γ), Δ40p53 (α, β, γ), Δ133p53 (α, β, γ), and Δ160p53 (α, β, γ). It has been shown that the p53 isoforms contribute to the regulation of the p53 pathway by regulating the expression of p53 target genes (Joruiz and Bourdon, 2016; Khoury and Bourdon, 2011; Zhao and Sanyal, 2022). Notably, p53 isoforms exhibit both overlapping and distinct functions compared to canonical p53 (Mehta et al., 2021; Pal et al., 2023; Zhao and Sanyal, 2022) and have been reported to promote tumor progression in various cancers (Vieler and Sanyal, 2018; Zhao and Sanyal, 2022). The p53 isoforms are generated through alternative promoter usage, alternative splicing, and alternative transcription starting site usage (Joruiz and Bourdon, 2016; Sharathchandra et al., 2014). These isoforms differ from the full-length (FL) p53 (canonical p53, p53α) by lacking variable segments of the N-terminus (N-terminal isoforms: Δ40, Δ133, and Δ160) and possessing alternative C-terminus (C-terminal isoforms: α, β, and γ). The FLp53 protein consists of four primary functional domains: transactivation domains (TAD-1 and TAD-2), DNA-binding core domain (DBD), nuclear localization sequence (NLS), and the oligomerization domain (OD) (Khoury and Bourdon, 2010). Native FLp53 typically functions as a tetrameric protein, where the individual monomers bind cooperatively to DNA (Jeffrey et al., 1995; Weinberg et al., 2004). The C-terminal truncated isoforms (β/γ isoforms) lacking the OD have lower transactivation activity because of reduced tetramerization efficiency (Jänicke et al., 2009; Kim et al., 2012; Wang et al., 1994; Wang et al., 1995). In contrast, the N-terminal truncated isoforms (α isoforms), which retain the entire C-terminal OD, can form various complexes with FLp53 and exert dominant-negative effects on p53’s transcriptional activity (Bourdon et al., 2005; Fujita et al., 2009; Horikawa et al., 2017). This study focuses on two large N-terminal deleted p53 isoforms: Δ133p53α and Δ160p53α, the latter has been largely unexplored. For convenience and simplicity, we have written Δ133p53 and Δ160p53 to represent the α isoforms (Δ133p53α and Δ160p53α) throughout this manuscript. The Δ133p53 protein lacks both TADs and a part of the first conserved cysteine box of the DBD, whereas the Δ160p53 protein lacks both TADs and the entire first conserved cysteine box of the DBD (Joruiz and Bourdon, 2016; Pavletich et al., 1993).

The Δ133p53 isoform exhibits complex biological functions, with both oncogenic and non-oncogenic potentials. Recent studies demonstrate the non-oncogenic yet context-dependent role of the Δ133p53 isoform in cancer development. Δ133p53 expression has been reported to correlate with improved survival in patients with TP53 mutations (Bischof et al., 2019; Hofstetter et al., 2011), where it promotes cell survival in a non-oncogenic manner (Gong et al., 2015; Gong et al., 2016b), especially under low oxidative stress (Gong et al., 2016c). Alternatively, other recent evidence emphasizes the notable oncogenic functions of Δ133p53 as it can inhibit p53-dependent apoptosis by directly interacting with the FLp53 (Aoubala et al., 2011; Bourdon et al., 2005). The oncogenic function of the newly identified Δ160p53 isoform is less known, although it is associated with p53 mutation-driven tumorigenesis (Candeias et al., 2016) and in melanoma cells’ aggressiveness (Tadijan et al., 2021). Whether or not the Δ160p53 isoform also impedes FLp53 function in a similar way as Δ133p53 is an open question. However, these p53 isoforms can certainly compromise p53-mediated tumor suppression by interfering with FLp53 binding to target genes such as p21 and miR-34a (Fujita et al., 2009; Horikawa et al., 2017) by dominant-negative effect, and the exact mechanism is not known.

Protein aggregation has become a central focus of modern biology research and has documented implications in various diseases, including cancer (Farmer et al., 2020; Forget et al., 2013; Petronilho et al., 2024). Protein aggregates can be of different types, ranging from amorphous aggregates to highly structured amyloid or fibrillar aggregates, each with different physiological implications. In the case of p53, whether protein aggregation, and, in particular, co-aggregation with large N-terminal deletion isoforms, plays a mechanistic role in its inactivation is yet underexplored. Interestingly, the Δ133p53β isoform has been shown to aggregate in several human cancer cell lines (Arsic et al., 2021). Additionally, the Δ40p53α isoform exhibits a high aggregation tendency in endometrial cancer cells (Melo Dos Santos et al., 2019). Although no direct evidence exists for Δ160p53 yet, these findings imply that p53 isoform aggregation may play a major role in their mechanisms of actions.

The precise molecular mechanisms involved in the biological function of the Δ133p53 and the Δ160p53 proteins, especially how they exert dominant-negative effects on FLp53, remain poorly understood. In this study, we have analyzed the DNA-binding, transcriptional activity, and oligomerization capacity of the human FLp53, Δ133p53, and Δ160p53 proteins. Our data show that the Δ133p53 and Δ160p53 proteins are deficient in binding to p53-regulated promoters and inducing expression of the p53 target genes. Moreover, the Δ133p53 and Δ160p53 isoforms can form hetero-oligomers with FLp53 and inhibit FLp53 function in a concentration-dependent manner. Two potential mechanisms for their dominant-negative effects have been suggested: (i) the formation of hetero-tetramers with FLp53, inhibiting its DNA-binding and transcriptional activity, and (ii) the aggregation property of the isoforms leading to co-aggregation of the FLp53 protein. Interestingly, while hetero-tetramerization partially attenuates p53 activity, the co-aggregation of FLp53 with Δ133p53 and Δ160p53 emerges as the predominant factor contributing to the dominant-negative effect.

The inactivation of p53 is one of the most common events in cancer cells (Kussie et al., 1996). Although functionally compromised p53 mutations are prevalent in more than half of human cancers (Bykov et al., 2018; Hollstein et al., 1991), specific p53 isoforms have recently been associated with tumorigenesis in various cancer types (Vieler and Sanyal, 2018; Zhao and Sanyal, 2022). The aberrant expression of Δ133p53 has been found in colorectal cancer (Campbell et al., 2018; Fujita et al., 2009) and lung cancer (Fragou et al., 2017). In comparison, the oncogenic role of the Δ160p53 isoform in human cancers is less explored (Zhao and Sanyal, 2022), although links have been established between the expression of the Δ160p53 isoform and melanoma cells (Tadijan et al., 2021). The mechanisms of the oncogenic potential of p53 isoforms have attracted attention from researchers (Arsic et al., 2021; Gong and Chen, 2016a; Lei et al., 2019; Melo Dos Santos et al., 2019; Mondal et al., 2013; Vieler and Sanyal, 2018). A theory of the dominant-negative effect has been introduced, but its exact details have remained unknown.

The ChIP and luciferase activity assays show that the isoforms Δ133p53 and Δ160p53 are defective in their ability to bind DNA and activate transcription (Figures 3B and 4A–D). A possible reason for the diminished DNA-binding function of these isoforms is that their core domains are defective (Figure 1B). The Δ133p53 and Δ160p53 isoforms lack approximately 20% and 33% of the DBD, which hinders their ability to bind to p53REs. We find that co-expression of Δ133p53 and Δ160p53 with FLp53 exerts an inhibitory effect on FLp53’s DNA-binding ability (Figure 3C). However, the degree to which Δ133p53 and Δ160p53 impair FLp53 function is influenced by both the expression levels of these isoforms and the specific promoters of the target genes (Figure 4). For the p21 and MDM2 promoters, equal expression of FLp53 and the two isoforms didn’t show much effect. However, higher expression levels of the isoforms gradually inhibited FLp53’s activity to induce transcription from those promoters (Figure 4A and B). Notably, the PUMA promoter behaved differently, whereby 1:1 co-expression of FLp53 with Δ133p53 or Δ160p53 significantly increased its activity (Figure 4D). We speculate that this isoform expression level may activate p21 induction pathways independent of FLp53 (Karimian et al., 2016), potentially facilitating the interaction between FLp53 and p21, which is required for optimal activation of PUMA promoter activity (Kim et al., 2022). These results underscore a complex regulatory network where FLp53 and the isoform expression levels, target gene specificity, and transcriptional activities modulate p53-mediated cellular responses.

Our co-expression data clearly indicate that the isoforms Δ133p53 and Δ160p53 exert a dominant-negative effect on FLp53 function (Figures 3, 4, and 7). Since both of these p53 isoforms are defective in DNA binding and they possess an intact C-terminal OD, it is not unexpected that they form different species of homo- and hetero-tetramers with FLp53. In accordance with that, the immunoprecipitation assays using FLAG-tagged FLp53 and V5-tagged/untagged Δ133p53 or Δ160p53 demonstrate a potential direct interaction between these isoforms and FLp53 (Figure 2A, lanes 7 and 8 and Figure 2—figure supplement 1, lanes 3 and 4). However, in what ratio the p53 isoforms impose inhibition to FLp53 function is worth investigating. We employed a theoretical model of p53 hetero-tetramer activity in transcriptional activation from p21, MDM2, BAX, and PUMA promoters by varying relative expression levels of the isoforms (Chan et al., 2004; Figure 4—figure supplement 1). We assumed that the transfection level was a good proxy for the expression level. Interestingly, the experimental inhibition curves with Δ133p53 or Δ160p53 derived from the luciferase reporter assay were all above the theoretical inhibition curves for two isoform molecules per tetramer (Figure 4—figure supplement 1B–E), suggesting that at least three isoform molecules per tetramer are required to abolish the transcriptional activity of FLp53. This is similar to an earlier report with Δ40p53 isoform, which was shown to exert a dominant-negative effect at a 3:1 ratio with FLp53 (Hafsi et al., 2013).

Interestingly, similar to Δ40p53 (Melo Dos Santos et al., 2019), the Δ133p53 and Δ160p53 proteins can aggregate in the cytoplasm (Figures 5C and 6E). Due to cytoplasmic aggregation and a stronger tendency for cytoplasmic localization (Figure 5), only a limited amount of these isoforms can successfully be imported into the nucleus. Additionally, the isoforms tend to aggregate within the nucleus (Figure 6B and E). Consequently, the ratio of these isoforms to FLp53 diminishes in the nucleus in contrast to their expression levels. This decrease reduces the likelihood of forming hetero-tetramers, in which the isoforms will be in higher proportion than FLp53. Thus, it seems unlikely that hetero-tetramerization of Δ133p53 and Δ160p53 isoforms with FLp53 would be the main reason for their dominant-negative effect.

Next, we investigated whether aggregation of the Δ133p53 and Δ160p53 isoforms contributes to their functional loss and dominant-negative effect on FLp53. Our immunofluorescence and immunoprecipitation analyses of H1299 cells expressing these isoforms show a higher aggregation propensity of the two isoforms than FLp53 (Figure 5C, Figure 1—figure supplement 2). The aggregation likely results from the exposure of hydrophobic sequences in the isoforms (Figure 1C). In addition, the absence of N-terminal TADs in Δ133p53 and Δ160p53 isoforms may prevent their MDM2-mediated ubiquitin-proteasome degradation (Chen et al., 1993; Kussie et al., 1996). This may, in turn, lead to higher accumulation of Δ133p53 and Δ160p53 isoforms in the cell, which, combined with an unstable core domain, promotes their aggregation. Moreover, the observed cytoplasmic isoform aggregates may reflect autophagy-related degradation, as suggested by the co-localization of Δ133p53 with autophagy substrate p62/SQSTM1 and autophagosome component LC3B (Horikawa et al., 2014). Overexpression of these aggregation-prone proteins could induce endoplasmic reticulum stress and activate autophagy (Lee et al., 2012). Interestingly, we also observed nuclear aggregation of these isoforms (Figure 6B, Figure 6—figure supplement 2), suggesting that distinct mechanisms, such as intrinsic properties of the isoforms, may govern their localization and behavior within the nucleus. This dual localization underscores the complexity of Δ133p53 and Δ160p53 behavior in cellular systems.

More interestingly, our immunofluorescence and immunoprecipitation assays demonstrate large co-aggregation of FLp53 with Δ133p53 and Δ160p53 isoforms in the cytoplasm as well as in the nucleus when expressed together (Figure 6E, Figure 6—figure supplement 3). The predominant cytoplasmic aggregation would sequester FLp53 in the cytoplasm. Moreover, it may destabilize FLp53’s conformation, potentially masking the NLS and preventing its nuclear import (Marine, 2010). Additionally, it may disrupt the interaction of FLp53 with MDM2, thereby inhibiting its MDM2-induced degradation and enhancing its accumulation (Moll and Petrenko, 2003), which would drive it more to the aggregation pathway. All these processes involving FLp53 aggregation would result in a reduction of the functional FLp53 in the cell and, more importantly, in the nucleus. Cytoplasmic aggregation would also limit the isoforms from nuclear import, reducing the possibility of hetero-tetramerization. Therefore, we propose that the co-aggregation of Δ133p53 and Δ160p53 with FLp53 is the primary factor for their dominant-negative effect. This mechanism is consistent with the model where structural mutations, such as R175H and R282W in FLp53, induce co-aggregation and exert a dominant-negative effect (Xu et al., 2011).

In our study, we primarily utilized an overexpression strategy involving FLAG/V5-tagged proteins to investigate the effects of p53 isoforms Δ133p53 and Δ160p53 on the function of FLp53. To address concerns regarding potential overexpression artifacts, we performed the co-immunoprecipitation (Figure 6—figure supplement 2) and caspase-3 and -7 activity (Figure 7) experiments with untagged Δ133p53 and Δ160p53. In both experimental systems, the untagged proteins behaved very similarly to the FLAG/V5 antibody epitope-containing proteins (Figures 6 and 7, Figure 6—figure supplement 2). Hence, the C-terminal tagging of FLp53 or its isoforms does not alter the biochemical and physiological functions of these proteins.

We propose a model to explain how the p53 isoforms Δ133p53 and Δ160p53 inhibit FLp53 activity and exert a dominant-negative effect on it (Figure 8A). Two mechanisms are involved: a subsidiary mechanism in which Δ133p53 and Δ160p53 isoforms form hetero-tetramers with FLp53, impairing its DNA-binding and transcriptional activities, and a predominant mechanism in which these isoforms promote co-aggregation with FLp53 and abolish its transcriptional activities by disrupting its structure, regulation, and degradation pathways. Since elevated levels of Δ133p53 and Δ160p53 relative to FLp53 attenuate its transcriptional activity (Figure 8B, left), and overexpression of FLp53 relative to the isoforms allows regaining it (Figure 8B, right), the tumor-suppressive efficacy of p53 must depend on the balanced expression of FLp53 and its isoforms, highlighting the importance of their relative abundance in cancer cells. Based on our results and recent related publications (Arsic et al., 2021; Melo Dos Santos et al., 2019), we propose that co-aggregation, rather than hetero-tetramerization, is the primary mechanism for the dominant-negative effect exerted by the p53 isoforms with large N-terminal truncations.

Figure 8

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All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 2–7, Figure 1—figure supplement 2, Figure 2—figure supplement 1, Figure 5—figure supplement 1, and Figure 6—figure supplement 1–3. All source data files are available in Zenodo Data Platform (Dataset DOI: https://doi.org/10.5281/zenodo.15688023).

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Author details

1. Liuqun Zhao

   Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Uppsala, Sweden

   Contribution

   Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Contributed equally with

   Tanel Punga

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0948-0923

2. Tanel Punga

   Department of Medical Biochemistry and Microbiology, Uppsala University, Biomedical Center, Uppsala, Sweden

   Contribution

   Data curation, Formal analysis, Supervision, Visualization, Methodology, Writing – review and editing

   Contributed equally with

   Liuqun Zhao

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0561-367X

3. Suparna Sanyal

   Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Uppsala, Sweden

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Investigation, Project administration, Writing – review and editing, Resources

   For correspondence

   suparna.sanyal@icm.uu.se

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7124-792X

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