International Journal of Molecular Sciences

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Open AccessEditorial

p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell

by Dennis Rangno and Przemyslaw Bozko

Int. J. Mol. Sci. 2026, 27(18), 8233; https://doi.org/10.3390/ijms27188233 - 16 Sep 2026

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Abstract

More than four decades after its discovery, p53 remains a central regulator of cellular homeostasis and one of the most extensively studied proteins in cancer biology [...] Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

Research

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20 pages, 1885 KB

Open AccessArticle

Proteomic Analysis of TCGA Data Reveals Limited Prognostic Value of p53 but Suggests BAX as a Potential Survival Marker in Cervical Carcinoma

by Sebastian M. Toennießen-Klein, Dennis Rangno, Abhirami Sunil, Maria Bozko and Przemyslaw Bozko

Int. J. Mol. Sci. 2026, 27(15), 6717; https://doi.org/10.3390/ijms27156717 - 27 Jul 2026

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Abstract

Cervical carcinoma is predominantly driven by high-risk human papillomavirus (HPV) infection, in which functional inactivation of p53 occurs mainly through viral oncoproteins rather than mutations in the TP53 gene. This raises questions concerning the prognostic relevance of TP53 gene status and p53 protein [...] Read more.

Cervical carcinoma is predominantly driven by high-risk human papillomavirus (HPV) infection, in which functional inactivation of p53 occurs mainly through viral oncoproteins rather than mutations in the TP53 gene. This raises questions concerning the prognostic relevance of TP53 gene status and p53 protein levels in this tumor type. This study aimed to systematically evaluate the prognostic significance of TP53 mutation status, p53 protein abundance, and selected downstream p53-regulated proteins in cervical carcinoma, with particular focus on tumors carrying wild-type TP53. Clinical and proteomic data from 162 cervical carcinoma patients were retrieved from The Cancer Genome Atlas (TCGA). Protein levels (p53, BAX, p21/CDKN1A, and TIGAR) were assessed using reverse-phase protein array (RPPA) data. Survival analyses were performed using Kaplan–Meier estimates with log-rank testing after stratification into quartile-based expression groups. The vast majority of tumors (~93%) harbored wild-type TP53, and the TP53 mutation status showed no association with patient survival. In tumors with wild-type TP53, p53 protein levels did not significantly correlate with overall survival, indicating a limited prognostic value. In contrast, elevated levels of the pro-apoptotic protein BAX showed a clear tendency to be associated with poorer overall and progression-free survival, suggesting BAX as a potential prognostic marker in this specific molecular context. The expression of p21/CDKN1A showed no prognostic relevance, while high TIGAR levels displayed a slight trend toward poorer survival, although without reaching statistical significance. In summary, in HPV-driven cervical carcinoma, neither the TP53 mutation status nor the p53 protein abundance reliably predict patient outcome. Instead, selected downstream effectors of p53 signaling—particularly BAX—may provide more informative prognostic insights in tumors retaining wild-type TP53. These findings highlight the importance of assessing functional outputs of p53 signaling rather than the p53 status alone in this disease context. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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24 pages, 4660 KB

Open AccessArticle

MK2/p38/p53 Suppress Basal IL-1β and Non-Canonical NF-κB Signaling in Macrophages

by Sarah M. Herr, Diana Stalkopf, Sofie Padaszus, Lukas A. Herbst, Anneke Dörrie, Rainer Niedenthal, Natalia Ronkina, Tatiana Yakovleva, Alexey Kotlyarov and Matthias Gaestel

Int. J. Mol. Sci. 2026, 27(7), 3232; https://doi.org/10.3390/ijms27073232 - 2 Apr 2026

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Abstract

Interleukin (IL)-1β is a pro-inflammatory cytokine implicated in sterile inflammation and tumor development. Investigating the role of MAPKAP kinase 2 (MK2) in IL-1β processing, we found that Il1b mRNA and IL-1β protein levels were elevated in resting MK2-knockout (KO) macrophages and in [...] Read more.

Interleukin (IL)-1β is a pro-inflammatory cytokine implicated in sterile inflammation and tumor development. Investigating the role of MAPKAP kinase 2 (MK2) in IL-1β processing, we found that Il1b mRNA and IL-1β protein levels were elevated in resting MK2-knockout (KO) macrophages and in the serum of MK2/3 double-KO mice. This was linked to activation of the non-canonical NF-κB pathway in the absence of MK2 or its activator, p38α. Rescue by MK2, its kinase-inactive mutant MK2K79R, or p38α suppressed this pathway and reduced Il1b expression. We also observed decreased basal protein levels of tumor suppressor p53 in MK2- or p38α-deficient cells. Mechanistically, p53 interacts with caspase-3, promoting cleavage of RelB, thereby inhibiting non-canonical NF-κB signaling and subsequent Il1b and TP53 expression. These findings explain elevated basal IL-1β levels in MK2-KO macrophages and uncover a new autoregulatory mechanism of TP53 expression. Additionally, they reveal a new mechanism that contributes to the long-discussed link between cancer and inflammation, wherein the tumor suppressor p53 inhibits cytokine production in parallel. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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18 pages, 1844 KB

Open AccessArticle

The Tumor Suppressor p53 Downregulates p107 (RBL1) Through p21–RB/E2F Signaling and Tandem E2F Sites

by Khaled Azzahrani and Faleh Alqahtani

Int. J. Mol. Sci. 2025, 26(20), 9903; https://doi.org/10.3390/ijms26209903 - 11 Oct 2025

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Abstract

RBL1 (p107) is a member of the retinoblastoma (RB) family of pocket proteins involved in cell cycle regulation and E2F transcriptional repression. While its promoter contains conserved E2F motifs, the integrated regulation of RBL1 by upstream tumor suppressor pathways remains incompletely understood. Here, [...] Read more.

RBL1 (p107) is a member of the retinoblastoma (RB) family of pocket proteins involved in cell cycle regulation and E2F transcriptional repression. While its promoter contains conserved E2F motifs, the integrated regulation of RBL1 by upstream tumor suppressor pathways remains incompletely understood. Here, we investigate the p53-dependent transcriptional regulation of RBL1 and dissect the contribution of its tandem E2F binding sites to this mechanism. Luciferase assays in synchronized cells demonstrated that these two conserved E2F sites are required for cell cycle-dependent activation of the RBL1 promoter. Overexpression of p53 showed that p53 represses RBL1 promoter activity in an E2F site-dependent manner. Using HCT116 p21 knockout cells, we revealed that this p53-dependent repression is mediated by p21. Chromatin immunoprecipitation confirmed dynamic in vivo binding of E2F1–3 and E2F4, while DNA pull-down assays revealed specific in vitro recruitment of RB, p107, and E2F1-4 to the two E2F sites, along with weak binding of MuvB components. Additional experiments in RB^–/– and LIN37^–/– knockouts showed that RB/E2F repressing complex plays the main role in repressing the RBL1 promoter, while E2F4, p107, and p130 can support this effect to a lesser extent. Overall, our findings demonstrate that p53 controls RBL1 expression indirectly through the p21–RB–E2F pathway by utilizing two E2F binding sites within the RBL1 promoter. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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13 pages, 1350 KB

Open AccessArticle

GnomAD Missense Variants of Uncertain Significance: Implications for p53 Stability and Phosphorylation

by Fernando Daniel García-Ayala, María de la Luz Ayala-Madrigal, Jorge Peregrina-Sandoval, José Miguel Moreno-Ortiz, Anahí González-Mercado and Melva Gutiérrez-Angulo

Int. J. Mol. Sci. 2025, 26(15), 7455; https://doi.org/10.3390/ijms26157455 - 1 Aug 2025

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Abstract

The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate [...] Read more.

The TP53 gene, frequently mutated across multiple cancer types, plays a pivotal role in regulating the cell cycle and apoptosis through its protein, p53. Missense variants of uncertain significance (VUSs) in TP53 present challenges in understanding their impact on protein function and complicate clinical interpretation. This study aims to analyze the effects of missense VUSs in p53, as reported in the gnomAD database, with a specific focus on their impact on protein stability and phosphorylation. In this study, 33 missense VUSs in TP53 reported in the gnomAD database were analyzed using in silico tools, including PhosphositePlus v6.7.4, the Kinase Library v0.0.11, and Dynamut2. Of these analyzed variants, five disrupted known phosphorylation sites, while another five created new consensus sequences for phosphorylation. Moreover, 20 variants exhibited a moderate destabilizing effect on the protein structure. At least three missense VUSs were identified as potentially affecting p53 function, which may contribute to cancer development. These findings highlight the importance of integrating in silico structural and functional analysis to assess the pathogenic potential of missense VUSs. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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Review

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35 pages, 1290 KB

Open AccessReview

The p53 Isoforms as Potential Biomarkers in Different Cancer Entities

by Christine Supina Pavić, Anđela Horvat, Ana Tadijan, Janja Josić, Martina Deželjin, Maja Jazvinšćak Jembrek, Ignacija Vlašić and Neda Slade

Int. J. Mol. Sci. 2026, 27(12), 5153; https://doi.org/10.3390/ijms27125153 - 6 Jun 2026

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Abstract

The p53 protein is a pivotal tumor suppressor that is mutated in more than half of tumor cases in humans. In addition, its activity/function can be perturbed by various other mechanisms. Existence of two promoters in the TP53 gene and extensive splicing on [...] Read more.

The p53 protein is a pivotal tumor suppressor that is mutated in more than half of tumor cases in humans. In addition, its activity/function can be perturbed by various other mechanisms. Existence of two promoters in the TP53 gene and extensive splicing on N- and C-terminus, as well as alternative translation initiation, give rise to numerous p53 protein isoforms. Different p53 protein isoforms can form heterotetramers with canonical full-length p53 or compete in binding target genes’ promoters as tetramers which can result in modulation of p53 function. In this review we have gathered the most novel research on the p53 isoform network including the isoforms’ expression profiles and biological functions in the most frequent cancer types. The expression of p53 isoforms differs among tumor types and compared with normal tissues, thereby affecting biological processes associated with tumorigenesis, such as apoptosis, cell cycle regulation, migration, senescence, stemness, etc. We also discussed the potential of targeting p53 isoforms by direct mechanisms that can change the ratio between specific isoforms and thus modulate their activity or indirectly by targeting downstream pathways regulated by a specific isoform. More profound understanding of the p53 pathway regulation could contribute to improvement in current therapies. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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Other

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7 pages, 340 KB

Open AccessCommentary

Harnessing p53 for Proximity Killing

by Joanna E. Zawacka

Int. J. Mol. Sci. 2026, 27(13), 5725; https://doi.org/10.3390/ijms27135725 - 25 Jun 2026

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Abstract

p53 tumor suppressor evolved as a critical player in navigating the response to environmental stresses such as DNA or oxidative damage and drives cell fate by governing life and death decisions. The p53 protein is encoded by the most commonly mutated gene in [...] Read more.

p53 tumor suppressor evolved as a critical player in navigating the response to environmental stresses such as DNA or oxidative damage and drives cell fate by governing life and death decisions. The p53 protein is encoded by the most commonly mutated gene in human cancers. TP53 gene mutations are associated with worse prognosis and refractory and relapsed disease. The most prevalent mutations are of the missense type and often result in disruption of the DNA-binding capacity and transcription activity. In healthy cells, p53 protein is tightly regulated by its E3 ubiquitin ligase, MDM2 (HDM2), its own transcription target. Mutant p53, therefore, escapes the regulation by the negative feedback loop and is often found upregulated in cancer cells. The efforts to exploit wild-type and mutant p53 for precision oncology have been ongoing in the last two decades yet have not been successful. A recently reported strategy to target TP53-mutant cancers leverages induced proximity, utilizing the high cellular abundance of mutant p53 as a scaffold to concentrate a small-molecule inhibitor against an essential survival protein. This strategy relies on the Regulated Induced Proximity TArgeting Chimera (RIPTAC). Given the recent FDA approval of the first chimeric drug, vepdegestrant, killing by proximity might turn out to be a promising medical advancement for precision oncology. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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10 pages, 895 KB

Open AccessOpinion

Latest News from the “Guardian”: p53 Directly Activates Asymmetric Stem Cell Division Regulators

by Ana Carmena

Int. J. Mol. Sci. 2025, 26(7), 3171; https://doi.org/10.3390/ijms26073171 - 29 Mar 2025

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Abstract

Since its discovery in 1979, the human tumor suppressor gene TP53—also known as the “guardian of the genome”—has been the subject of intense research. Mutated in most human cancers, TP53 has traditionally been considered a key fighter against stress factors by trans-activating [...] Read more.

Since its discovery in 1979, the human tumor suppressor gene TP53—also known as the “guardian of the genome”—has been the subject of intense research. Mutated in most human cancers, TP53 has traditionally been considered a key fighter against stress factors by trans-activating a network of target genes that promote cell cycle arrest, DNA repair, or apoptosis. Intriguingly, over the past years, novel non-canonical functions of p53 in unstressed cells have also emerged, including the mode of stem cell division regulation. However, the mechanisms by which p53 modulates these novel functions remain incompletely understood. In a recent work, we found that Drosophila p53 controls asymmetric stem cell division (ASCD) in neural stem cells by transcriptionally activating core ASCD regulators, such as the conserved cell-fate determinants Numb and Brat (NUMB and TRIM3/TRIM2/TRIM32 in humans, respectively). In this short communication, we comment on this new finding, the mild phenotypes associated with Drosophila p53 mutants in this context, as well as novel avenues for future research. Full article

(This article belongs to the Special Issue p53—Oncogene, Tumor Suppressor Gene, Guardian of the Genome and the Cell)

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